ID BACE2_HUMAN Reviewed; 518 AA. AC Q9Y5Z0; A8K7P1; Q5DIH8; Q8N2D4; Q9H2V8; Q9NZL1; Q9NZL2; Q9UJT6; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1999, sequence version 1. DT 28-JAN-2026, entry version 215. DE RecName: Full=Beta-secretase 2; DE EC=3.4.23.45 {ECO:0000269|PubMed:21907142}; DE AltName: Full=Aspartic-like protease 56 kDa; DE AltName: Full=Aspartyl protease 1; DE Short=ASP1; DE Short=Asp 1; DE AltName: Full=Beta-site amyloid precursor protein cleaving enzyme 2; DE Short=Beta-site APP cleaving enzyme 2; DE AltName: Full=Down region aspartic protease; DE Short=DRAP; DE AltName: Full=Memapsin-1; DE AltName: Full=Membrane-associated aspartic protease 1; DE AltName: Full=Theta-secretase; DE Flags: Precursor; GN Name=BACE2; Synonyms=AEPLC, ALP56, ASP21; ORFNames=CDA13, UNQ418/PRO852; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF N-TERMINUS, RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=10591213; DOI=10.1038/990107; RA Yan R., Bienkowski M.J., Shuck M.E., Miao H., Tory M.C., Pauley A.M., RA Brashier J.R., Stratman N.C., Mathews W.R., Buhl A.E., Carter D.B., RA Tomasselli A.G., Parodi L.A., Heinrikson R.L., Gurney M.E.; RT "Membrane-anchored aspartyl protease with Alzheimer's disease beta- RT secretase activity."; RL Nature 402:533-537(1999). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AUTOCATALYTIC CLEAVAGE, INDUCTION, RP TISSUE SPECIFICITY, AND MUTAGENESIS OF ASP-110 AND ASP-303. RC TISSUE=Bone marrow; RX PubMed=10838186; DOI=10.1016/s0925-4439(00)00014-4; RA Xin H., Stephans J.C., Duan X., Harrowe G., Kim E., Grieshammer U., RA Kingsley C., Giese K.; RT "Identification of a novel aspartic-like protease differentially expressed RT in human breast cancer cell lines."; RL Biochim. Biophys. Acta 1501:125-137(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3), AND TISSUE SPECIFICITY. RX PubMed=10965118; DOI=10.1159/000015608; RA Solans A., Estivill X., de La Luna S.; RT "A new aspartyl protease on 21q22.3, BACE2, is highly similar to RT Alzheimer's amyloid precursor protein beta-secretase."; RL Cytogenet. Cell Genet. 89:177-184(2000). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND RP GLYCOSYLATION. RX PubMed=10683441; DOI=10.1016/s0014-5793(00)01192-3; RA Acquati F., Accarino M.P., Nucci C., Fumagalli P., Jovine L., RA Ottolenghi S., Taramelli R.; RT "The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of RT the aspartic protease family, maps to the down critical region."; RL FEBS Lett. 468:59-64(2000). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY. RX PubMed=10749877; DOI=10.1074/jbc.m002688200; RA Bennett B.D., Babu-Khan S., Loeloff R., Louis J.-C., Curran E., Citron M., RA Vassar R.; RT "Expression analysis of BACE2 in brain and peripheral tissues."; RL J. Biol. Chem. 275:20647-20651(2000). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF N-TERMINUS, RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, GLYCOSYLATION, AND RP CATALYTIC ACTIVITY. RX PubMed=11083922; DOI=10.1006/mcne.2000.0884; RA Hussain I., Powell D.J., Howlett D.R., Chapman G.A., Gilmour L., RA Murdock P.R., Tew D.G., Meek T.D., Chapman C., Schneider K., RA Ratcliffe S.J., Tattersall D., Testa T.T., Southan C., Ryan D.M., RA Simmons D.L., Walsh F.S., Dingwall C., Christie G.; RT "ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase RT site."; RL Mol. Cell. Neurosci. 16:609-619(2000). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY. RX PubMed=10677483; DOI=10.1073/pnas.97.4.1456; RA Lin X., Koelsch G., Wu S., Downs D., Dashti A., Tang J.; RT "Human aspartic protease memapsin 2 cleaves the beta-secretase site of RT beta-amyloid precursor protein."; RL Proc. Natl. Acad. Sci. U.S.A. 97:1456-1460(2000). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4). RC TISSUE=Pheochromocytoma; RA Li Y., Huang Q., Peng Y., Song H., Yu Y., Xu S., Ren S., Chen Z., Han Z.; RL Submitted (DEC-1999) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RX PubMed=12975309; DOI=10.1101/gr.1293003; RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A., RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.; RT "The secreted protein discovery initiative (SPDI), a large-scale effort to RT identify novel human secreted and transmembrane proteins: a bioinformatics RT assessment."; RL Genome Res. 13:2265-2270(2003). RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 5). RC TISSUE=Ovary, and Stomach; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=10830953; DOI=10.1038/35012518; RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S., RA Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M., RA Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A., Menzel U., RA Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A., RA Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J., RA Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K., RA Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G., RA Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J., RA Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S., RA Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K., RA Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L.; RT "The DNA sequence of human chromosome 21."; RL Nature 405:311-319(2000). RN [12] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [13] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [14] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-47, AND FUNCTION. RX PubMed=15857888; DOI=10.1096/fj.04-3426com; RA Sun X., Wang Y., Qing H., Christensen M.A., Liu Y., Zhou W., Tong Y., RA Xiao C., Huang Y., Zhang S., Liu X., Song W.; RT "Distinct transcriptional regulation and function of the human BACE2 and RT BACE1 genes."; RL FASEB J. 19:739-749(2005). RN [15] RP PROTEIN SEQUENCE OF N-TERMINUS, AUTOCATALYTIC CLEAVAGE, FUNCTION, AND RP SUBCELLULAR LOCATION. RX PubMed=11423558; DOI=10.1074/jbc.m105583200; RA Yan R., Munzner J.B., Shuck M.E., Bienkowski M.J.; RT "BACE2 functions as an alternative alpha-secretase in cells."; RL J. Biol. Chem. 276:34019-34027(2001). RN [16] RP PROTEIN SEQUENCE OF N-TERMINUS, AND FUNCTION. RX PubMed=16816112; DOI=10.1096/fj.05-5632com; RA Sun X., He G., Song W.; RT "BACE2, as a novel APP theta-secretase, is not responsible for the RT pathogenesis of Alzheimer's disease in Down syndrome."; RL FASEB J. 20:1369-1376(2006). RN [17] RP PROTEIN SEQUENCE OF N-TERMINUS, X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF RP 78-460, SUBUNIT, AND DISULFIDE BONDS. RX PubMed=16305800; DOI=10.1016/j.jmb.2005.10.027; RA Ostermann N., Eder J., Eidhoff U., Zink F., Hassiepen U., Worpenberg S., RA Maibaum J., Simic O., Hommel U., Gerhartz B.; RT "Crystal structure of human BACE2 in complex with a hydroxyethylamine RT transition-state inhibitor."; RL J. Mol. Biol. 355:249-261(2006). RN [18] RP AUTOCATALYTIC CLEAVAGE, AND MUTAGENESIS OF ASP-110. RX PubMed=11316808; DOI=10.1074/jbc.m101069200; RA Hussain I., Christie G., Schneider K., Moore S., Dingwall C.; RT "Prodomain processing of Asp1 (BACE2) is autocatalytic."; RL J. Biol. Chem. 276:23322-23328(2001). RN [19] RP INTERACTION WITH RTN3 AND RTN4. RX PubMed=16965550; DOI=10.1111/j.1460-9568.2006.05005.x; RA Murayama K.S., Kametani F., Saito S., Kume H., Akiyama H., Araki W.; RT "Reticulons RTN3 and RTN4-B/C interact with BACE1 and inhibit its ability RT to produce amyloid beta-protein."; RL Eur. J. Neurosci. 24:1237-1244(2006). RN [20] RP SUBCELLULAR LOCATION, FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=21907142; DOI=10.1016/j.cmet.2011.06.018; RA Esterhazy D., Stuetzer I., Wang H., Rechsteiner M.P., Beauchamp J., RA Doebeli H., Hilpert H., Matile H., Prummer M., Schmidt A., Lieske N., RA Boehm B., Marselli L., Bosco D., Kerr-Conte J., Aebersold R., Spinas G.A., RA Moch H., Migliorini C., Stoffel M.; RT "Bace2 is a beta cell-enriched protease that regulates pancreatic beta cell RT function and mass."; RL Cell Metab. 14:365-377(2011). RN [21] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=23754390; DOI=10.1073/pnas.1220748110; RA Rochin L., Hurbain I., Serneels L., Fort C., Watt B., Leblanc P., RA Marks M.S., De Strooper B., Raposo G., van Niel G.; RT "BACE2 processes PMEL to form the melanosome amyloid matrix in pigment RT cells."; RL Proc. Natl. Acad. Sci. U.S.A. 110:10658-10663(2013). CC -!- FUNCTION: Responsible for the proteolytic processing of the amyloid CC precursor protein (APP). Cleaves APP, between residues 690 and 691, CC leading to the generation and extracellular release of beta-cleaved CC soluble APP, and a corresponding cell-associated C-terminal fragment CC which is later released by gamma-secretase. It has also been shown that CC it can cleave APP between residues 671 and 672 (PubMed:10591213, CC PubMed:11083922, PubMed:11423558, PubMed:15857888, PubMed:16816112). CC Involved in the proteolytic shedding of PMEL at early stages of CC melanosome biogenesis. Cleaves PMEL within the M-beta fragment to CC release the amyloidogenic PMEL luminal fragment containing M-alpha and CC a small portion of M-beta N-terminus. This is a prerequisite step for CC subsequent processing and assembly of PMEL fibrils into amyloid sheets CC (PubMed:23754390). Responsible also for the proteolytic processing of CC CLTRN in pancreatic beta cells (PubMed:21907142). CC {ECO:0000269|PubMed:10591213, ECO:0000269|PubMed:11083922, CC ECO:0000269|PubMed:11423558, ECO:0000269|PubMed:15857888, CC ECO:0000269|PubMed:16816112, ECO:0000269|PubMed:21907142, CC ECO:0000269|PubMed:23754390}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Broad endopeptidase specificity. Cleaves Glu-Val-Asn-Leu-|- CC Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid CC precursor protein.; EC=3.4.23.45; CC Evidence={ECO:0000269|PubMed:11083922, ECO:0000269|PubMed:21907142}; CC -!- SUBUNIT: Monomer. Interacts with RTN3 and RTN4. CC {ECO:0000269|PubMed:16305800, ECO:0000269|PubMed:16965550}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:21907142}; CC Single-pass type I membrane protein {ECO:0000255}. Golgi apparatus CC {ECO:0000269|PubMed:11423558}. Endoplasmic reticulum. Endosome. CC Melanosome {ECO:0000269|PubMed:23754390}. Note=Colocalizes with PMEL in CC stage I and II melanosomes. {ECO:0000269|PubMed:23754390}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=5; CC Name=1; Synonyms=Isoform A; CC IsoId=Q9Y5Z0-1; Sequence=Displayed; CC Name=2; Synonyms=Isoform C; CC IsoId=Q9Y5Z0-2; Sequence=VSP_038025; CC Name=3; Synonyms=Isoform B; CC IsoId=Q9Y5Z0-3; Sequence=VSP_038026, VSP_038027; CC Name=4; CC IsoId=Q9Y5Z0-4; Sequence=VSP_038024; CC Name=5; CC IsoId=Q9Y5Z0-5; Sequence=VSP_038023; CC -!- TISSUE SPECIFICITY: Brain. Present in neurons within the hippocampus, CC frontal cortex and temporal cortex (at protein level). Expressed at low CC levels in most peripheral tissues and at higher levels in colon, CC kidney, pancreas, placenta, prostate, stomach and trachea. Expressed at CC low levels in the brain. Found in spinal cord, medulla oblongata, CC substantia nigra and locus coruleus. Expressed in the ductal epithelium CC of both normal and malignant prostate. {ECO:0000269|PubMed:10591213, CC ECO:0000269|PubMed:10677483, ECO:0000269|PubMed:10683441, CC ECO:0000269|PubMed:10749877, ECO:0000269|PubMed:10838186, CC ECO:0000269|PubMed:10965118, ECO:0000269|PubMed:11083922}. CC -!- INDUCTION: Up-regulated in primary breast and colon tumors and liver CC metastasis. {ECO:0000269|PubMed:10838186}. CC -!- PTM: Undergoes autoproteolytic cleavage. {ECO:0000269|PubMed:11316808, CC ECO:0000269|PubMed:11423558}. CC -!- PTM: Glycosylated. {ECO:0000269|PubMed:10683441, CC ECO:0000269|PubMed:11083922}. CC -!- SIMILARITY: Belongs to the peptidase A1 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF200342; AAF17078.1; -; mRNA. DR EMBL; AF117892; AAD45240.1; -; mRNA. DR EMBL; AF178532; AAF29494.1; -; mRNA. DR EMBL; AF188276; AAF35835.1; -; mRNA. DR EMBL; AF188277; AAF35836.1; -; mRNA. DR EMBL; AF050171; AAD45963.1; -; mRNA. DR EMBL; AF204944; AAF26368.1; -; mRNA. DR EMBL; AF200192; AAF13714.1; -; mRNA. DR EMBL; AF212252; AAG41783.1; -; mRNA. DR EMBL; AY358927; AAQ89286.1; -; mRNA. DR EMBL; AK075539; BAC11682.1; -; mRNA. DR EMBL; AK292056; BAF84745.1; -; mRNA. DR EMBL; AL163284; CAB90458.1; -; Genomic_DNA. DR EMBL; AL163285; CAB90554.1; -; Genomic_DNA. DR EMBL; CH471079; EAX09611.1; -; Genomic_DNA. DR EMBL; CH471079; EAX09613.1; -; Genomic_DNA. DR EMBL; BC014453; AAH14453.1; -; mRNA. DR EMBL; AY769996; AAX14808.1; -; Genomic_DNA. DR CCDS; CCDS13668.1; -. [Q9Y5Z0-1] DR CCDS; CCDS13669.1; -. [Q9Y5Z0-2] DR CCDS; CCDS13670.1; -. [Q9Y5Z0-3] DR RefSeq; NP_036237.2; NM_012105.4. [Q9Y5Z0-1] DR RefSeq; NP_620476.1; NM_138991.3. [Q9Y5Z0-2] DR RefSeq; NP_620477.1; NM_138992.3. [Q9Y5Z0-3] DR PDB; 2EWY; X-ray; 3.10 A; A/B/C/D=78-460. DR PDB; 3ZKG; X-ray; 1.90 A; A/B=75-460. DR PDB; 3ZKI; X-ray; 2.40 A; A/B=75-460. DR PDB; 3ZKM; X-ray; 1.85 A; A/B=75-460. DR PDB; 3ZKN; X-ray; 2.00 A; A/B=75-460. DR PDB; 3ZKQ; X-ray; 1.51 A; A=75-460. DR PDB; 3ZKS; X-ray; 2.11 A; A=75-460. DR PDB; 3ZKX; X-ray; 2.37 A; A=75-460. DR PDB; 3ZL7; X-ray; 3.20 A; A=75-460. DR PDB; 3ZLQ; X-ray; 2.10 A; A/B=75-460. DR PDB; 4BEL; X-ray; 1.85 A; A/B=75-460. DR PDB; 4BFB; X-ray; 2.21 A; A/B=75-460. DR PDB; 6JSZ; X-ray; 1.53 A; A=75-460. DR PDB; 6UJ0; X-ray; 2.15 A; A/B=1-460. DR PDB; 6UJ1; X-ray; 3.03 A; A/B=1-460. DR PDB; 7D5B; X-ray; 1.31 A; A=75-460. DR PDB; 7D5U; X-ray; 2.04 A; A=75-460. DR PDB; 7F1G; X-ray; 1.50 A; A=75-460. DR PDB; 7N4N; X-ray; 1.41 A; A=75-460. DR PDBsum; 2EWY; -. DR PDBsum; 3ZKG; -. DR PDBsum; 3ZKI; -. DR PDBsum; 3ZKM; -. DR PDBsum; 3ZKN; -. DR PDBsum; 3ZKQ; -. DR PDBsum; 3ZKS; -. DR PDBsum; 3ZKX; -. DR PDBsum; 3ZL7; -. DR PDBsum; 3ZLQ; -. DR PDBsum; 4BEL; -. DR PDBsum; 4BFB; -. DR PDBsum; 6JSZ; -. DR PDBsum; 6UJ0; -. DR PDBsum; 6UJ1; -. DR PDBsum; 7D5B; -. DR PDBsum; 7D5U; -. DR PDBsum; 7F1G; -. DR PDBsum; 7N4N; -. DR AlphaFoldDB; Q9Y5Z0; -. DR SMR; Q9Y5Z0; -. DR BioGRID; 117353; 107. DR FunCoup; Q9Y5Z0; 666. DR MINT; Q9Y5Z0; -. DR STRING; 9606.ENSP00000332979; -. DR BindingDB; Q9Y5Z0; -. DR ChEMBL; CHEMBL2525; -. DR GuidetoPHARMACOLOGY; 2331; -. DR MEROPS; A01.041; -. DR TCDB; 8.A.32.1.2; the Beta-amyloid cleaving enzyme (bace1) family. DR GlyCosmos; Q9Y5Z0; 3 sites, 1 glycan. DR GlyGen; Q9Y5Z0; 6 sites, 3 N-linked glycans (2 sites), 2 O-linked glycans (3 sites). DR iPTMnet; Q9Y5Z0; -. DR PhosphoSitePlus; Q9Y5Z0; -. DR SwissPalm; Q9Y5Z0; -. DR BioMuta; BACE2; -. DR DMDM; 6685260; -. DR jPOST; Q9Y5Z0; -. DR MassIVE; Q9Y5Z0; -. DR PaxDb; 9606-ENSP00000332979; -. DR PeptideAtlas; Q9Y5Z0; -. DR ProteomicsDB; 86546; -. [Q9Y5Z0-1] DR ProteomicsDB; 86547; -. [Q9Y5Z0-2] DR ProteomicsDB; 86548; -. [Q9Y5Z0-3] DR ProteomicsDB; 86549; -. [Q9Y5Z0-4] DR ProteomicsDB; 86550; -. [Q9Y5Z0-5] DR Pumba; Q9Y5Z0; -. DR ABCD; Q9Y5Z0; 3 sequenced antibodies. DR Antibodypedia; 4410; 552 antibodies from 37 providers. DR DNASU; 25825; -. DR Ensembl; ENST00000328735.10; ENSP00000333854.6; ENSG00000182240.17. [Q9Y5Z0-3] DR Ensembl; ENST00000330333.11; ENSP00000332979.6; ENSG00000182240.17. [Q9Y5Z0-1] DR Ensembl; ENST00000347667.5; ENSP00000327528.4; ENSG00000182240.17. [Q9Y5Z0-2] DR GeneID; 25825; -. DR KEGG; hsa:25825; -. DR MANE-Select; ENST00000330333.11; ENSP00000332979.6; NM_012105.5; NP_036237.2. DR UCSC; uc002yyw.5; human. [Q9Y5Z0-1] DR AGR; HGNC:934; -. DR ClinPGx; PA25233; -. DR CTD; 25825; -. DR DisGeNET; 25825; -. DR GeneCards; BACE2; -. DR HGNC; HGNC:934; BACE2. DR HPA; ENSG00000182240; Tissue enhanced (salivary). DR MIM; 605668; gene. DR OpenTargets; ENSG00000182240; -. DR VEuPathDB; HostDB:ENSG00000182240; -. DR eggNOG; KOG1339; Eukaryota. DR GeneTree; ENSGT00940000159548; -. DR HOGENOM; CLU_039009_0_0_1; -. DR InParanoid; Q9Y5Z0; -. DR OMA; CDTVNDE; -. DR OrthoDB; 2747330at2759; -. DR PAN-GO; Q9Y5Z0; 6 GO annotations based on evolutionary models. DR PhylomeDB; Q9Y5Z0; -. DR BioCyc; MetaCyc:G66-33964-MONOMER; -. DR BRENDA; 3.4.23.45; 2681. DR BRENDA; 3.4.24.56; 2681. DR PathwayCommons; Q9Y5Z0; -. DR SignaLink; Q9Y5Z0; -. DR SIGNOR; Q9Y5Z0; -. DR Agora; ENSG00000182240; -. DR BioGRID-ORCS; 25825; 11 hits in 1151 CRISPR screens. DR ChiTaRS; BACE2; human. DR EvolutionaryTrace; Q9Y5Z0; -. DR GeneWiki; Beta-secretase_2; -. DR GenomeRNAi; 25825; -. DR Pharos; Q9Y5Z0; Tchem. DR PRO; PR:Q9Y5Z0; -. DR Proteomes; UP000005640; Chromosome 21. DR RNAct; Q9Y5Z0; protein. DR Bgee; ENSG00000182240; Expressed in parotid gland and 182 other cell types or tissues. DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell. DR GO; GO:0005768; C:endosome; IBA:GO_Central. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0033162; C:melanosome membrane; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; NAS:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0005802; C:trans-Golgi network; IBA:GO_Central. DR GO; GO:0004190; F:aspartic-type endopeptidase activity; IDA:UniProtKB. DR GO; GO:0050435; P:amyloid-beta metabolic process; IBA:GO_Central. DR GO; GO:0042593; P:glucose homeostasis; IMP:UniProtKB. DR GO; GO:0032438; P:melanosome organization; IMP:UniProtKB. DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IDA:UniProtKB. DR GO; GO:0042985; P:negative regulation of amyloid precursor protein biosynthetic process; IMP:UniProtKB. DR GO; GO:0016486; P:peptide hormone processing; NAS:UniProtKB. DR GO; GO:0016485; P:protein processing; IDA:UniProtKB. DR GO; GO:0006508; P:proteolysis; NAS:UniProtKB. DR CDD; cd05473; beta_secretase_like; 1. DR FunFam; 2.40.70.10:FF:000003; Beta-secretase 1; 1. DR FunFam; 2.40.70.10:FF:000007; Beta-secretase 1; 1. DR Gene3D; 2.40.70.10; Acid Proteases; 2. DR InterPro; IPR001461; Aspartic_peptidase_A1. DR InterPro; IPR001969; Aspartic_peptidase_AS. DR InterPro; IPR009119; BACE. DR InterPro; IPR009121; BACE2. DR InterPro; IPR033874; Memapsin-like. DR InterPro; IPR033121; PEPTIDASE_A1. DR InterPro; IPR021109; Peptidase_aspartic_dom_sf. DR PANTHER; PTHR47965; ASPARTYL PROTEASE-RELATED; 1. DR PANTHER; PTHR47965:SF40; BETA-SECRETASE 2; 1. DR Pfam; PF00026; Asp; 1. DR PRINTS; PR01817; BACE2. DR PRINTS; PR01815; BACEFAMILY. DR PRINTS; PR00792; PEPSIN. DR SUPFAM; SSF50630; Acid proteases; 1. DR PROSITE; PS00141; ASP_PROTEASE; 2. DR PROSITE; PS51767; PEPTIDASE_A1; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Aspartyl protease; KW Autocatalytic cleavage; Cell membrane; Direct protein sequencing; KW Disulfide bond; Endoplasmic reticulum; Endosome; Glycoprotein; KW Golgi apparatus; Hydrolase; Membrane; Protease; Proteomics identification; KW Reference proteome; Signal; Transmembrane; Transmembrane helix; Zymogen. FT SIGNAL 1..20 FT /evidence="ECO:0000255" FT PROPEP 21..62 FT /evidence="ECO:0000269|PubMed:10591213, FT ECO:0000269|PubMed:11083922, ECO:0000269|PubMed:11423558, FT ECO:0000269|PubMed:16305800, ECO:0000269|PubMed:16816112" FT /id="PRO_0000025945" FT CHAIN 63..518 FT /note="Beta-secretase 2" FT /id="PRO_0000025946" FT TOPO_DOM 21..473 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 474..494 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 495..518 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 92..429 FT /note="Peptidase A1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01103" FT ACT_SITE 110 FT ACT_SITE 303 FT CARBOHYD 170 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 366 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 233..433 FT /evidence="ECO:0000269|PubMed:16305800" FT DISULFID 292..457 FT /evidence="ECO:0000269|PubMed:16305800" FT DISULFID 344..393 FT /evidence="ECO:0000269|PubMed:16305800" FT VAR_SEQ 1..95 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_038023" FT VAR_SEQ 1..79 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|Ref.8" FT /id="VSP_038024" FT VAR_SEQ 329..378 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:10965118" FT /id="VSP_038025" FT VAR_SEQ 379..396 FT /note="LYIQPMMGAGLNYECYRF -> KLQVLQCLKFPGLSQQRM (in isoform FT 3)" FT /evidence="ECO:0000303|PubMed:10965118" FT /id="VSP_038026" FT VAR_SEQ 397..518 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:10965118" FT /id="VSP_038027" FT MUTAGEN 110 FT /note="D->A,N: Loss of autoproteolytic cleavage." FT /evidence="ECO:0000269|PubMed:10838186, FT ECO:0000269|PubMed:11316808" FT MUTAGEN 303 FT /note="D->A: Loss of autoproteolytic cleavage." FT /evidence="ECO:0000269|PubMed:10838186" FT CONFLICT 36 FT /note="A -> T (in Ref. 7; AAF13714)" FT /evidence="ECO:0000305" FT CONFLICT 184 FT /note="E -> G (in Ref. 10; BAC11682)" FT /evidence="ECO:0000305" FT CONFLICT 192 FT /note="K -> Q (in Ref. 10; BAC11682)" FT /evidence="ECO:0000305" FT CONFLICT 233 FT /note="C -> R (in Ref. 10; BAC11682)" FT /evidence="ECO:0000305" FT HELIX 78..80 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 84..87 FT /evidence="ECO:0007829|PDB:7D5B" FT TURN 88..90 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 91..98 FT /evidence="ECO:0007829|PDB:7D5B" FT TURN 99..102 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 103..110 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 116..119 FT /evidence="ECO:0007829|PDB:7D5B" FT HELIX 132..134 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 139..149 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 152..164 FT /evidence="ECO:0007829|PDB:7D5B" FT TURN 166..168 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 173..185 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 194..198 FT /evidence="ECO:0007829|PDB:7D5B" FT HELIX 202..204 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 206..208 FT /evidence="ECO:0007829|PDB:6UJ1" FT HELIX 214..222 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 228..232 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 247..253 FT /evidence="ECO:0007829|PDB:7D5B" FT HELIX 256..258 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 264..270 FT /evidence="ECO:0007829|PDB:7D5B" FT TURN 271..274 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 278..283 FT /evidence="ECO:0007829|PDB:7D5B" FT HELIX 292..295 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 296..298 FT /evidence="ECO:0007829|PDB:6JSZ" FT STRAND 300..302 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 308..312 FT /evidence="ECO:0007829|PDB:7D5B" FT HELIX 313..326 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 328..330 FT /evidence="ECO:0007829|PDB:7D5B" FT HELIX 334..337 FT /evidence="ECO:0007829|PDB:7D5B" FT HELIX 339..342 FT /evidence="ECO:0007829|PDB:3ZKN" FT STRAND 343..345 FT /evidence="ECO:0007829|PDB:7N4N" FT HELIX 347..349 FT /evidence="ECO:0007829|PDB:4BFB" FT HELIX 352..354 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 358..363 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 369..375 FT /evidence="ECO:0007829|PDB:7D5B" FT HELIX 377..379 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 381..383 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 393..403 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 405..407 FT /evidence="ECO:0007829|PDB:7D5B" FT HELIX 409..412 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 415..420 FT /evidence="ECO:0007829|PDB:7D5B" FT TURN 421..424 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 425..430 FT /evidence="ECO:0007829|PDB:7D5B" FT HELIX 432..434 FT /evidence="ECO:0007829|PDB:6UJ0" FT HELIX 436..438 FT /evidence="ECO:0007829|PDB:6UJ1" FT STRAND 439..449 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 451..453 FT /evidence="ECO:0007829|PDB:7F1G" FT CONFLICT Q9Y5Z0-3:381 FT /note="Q -> R (in Ref. 3; AAF35836)" FT /evidence="ECO:0000305" FT CONFLICT Q9Y5Z0-3:396 FT /note="M -> F (in Ref. 3; AAF35836)" FT /evidence="ECO:0000305" SQ SEQUENCE 518 AA; 56180 MW; 2E903150823760D3 CRC64; MGALARALLL PLLAQWLLRA APELAPAPFT LPLRVAAATN RVVAPTPGPG TPAERHADGL ALALEPALAS PAGAANFLAM VDNLQGDSGR GYYLEMLIGT PPQKLQILVD TGSSNFAVAG TPHSYIDTYF DTERSSTYRS KGFDVTVKYT QGSWTGFVGE DLVTIPKGFN TSFLVNIATI FESENFFLPG IKWNGILGLA YATLAKPSSS LETFFDSLVT QANIPNVFSM QMCGAGLPVA GSGTNGGSLV LGGIEPSLYK GDIWYTPIKE EWYYQIEILK LEIGGQSLNL DCREYNADKA IVDSGTTLLR LPQKVFDAVV EAVARASLIP EFSDGFWTGS QLACWTNSET PWSYFPKISI YLRDENSSRS FRITILPQLY IQPMMGAGLN YECYRFGISP STNALVIGAT VMEGFYVIFD RAQKRVGFAA SPCAEIAGAA VSEISGPFST EDVASNCVPA QSLSEPILWI VSYALMSVCG AILLVLIVLL LLPFRCQRRP RDPEVVNDES SLVRHRWK // ID CATD_HUMAN Reviewed; 412 AA. AC P07339; Q6IB57; DT 01-APR-1988, integrated into UniProtKB/Swiss-Prot. DT 01-APR-1988, sequence version 1. DT 28-JAN-2026, entry version 256. DE RecName: Full=Cathepsin D; DE EC=3.4.23.5; DE Contains: DE RecName: Full=Cathepsin D light chain; DE Contains: DE RecName: Full=Cathepsin D heavy chain; DE Flags: Precursor; GN Name=CTSD; Synonyms=CPSD; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=3927292; DOI=10.1073/pnas.82.15.4910; RA Faust P.L., Kornfeld S., Chirgwin J.M.; RT "Cloning and sequence analysis of cDNA for human cathepsin D."; RL Proc. Natl. Acad. Sci. U.S.A. 82:4910-4914(1985). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=3588310; DOI=10.1093/nar/15.9.3773; RA Westley B.R., May F.E.B.; RT "Oestrogen regulates cathepsin D mRNA levels in oestrogen responsive human RT breast cancer cells."; RL Nucleic Acids Res. 15:3773-3786(1987). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=2069717; DOI=10.1089/dna.1991.10.423; RA Redecker B., Heckendorf B., Grosch H.W., Mersmann G., Hasilik A.; RT "Molecular organization of the human cathepsin D gene."; RL DNA Cell Biol. 10:423-431(1991). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Kidney; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-22. RX PubMed=8262386; DOI=10.1016/0378-1119(93)90107-e; RA May F.E., Smith D.J., Westley B.R.; RT "The human cathepsin D-encoding gene is transcribed from an estrogen- RT regulated and a constitutive start point."; RL Gene 134:277-282(1993). RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-22. RX PubMed=7935485; DOI=10.1210/mend.8.6.7935485; RA Augereau P., Miralles F., Cavailles V., Gaudelet C., Parker M., RA Rochefort H.; RT "Characterization of the proximal estrogen-responsive element of human RT cathepsin D gene."; RL Mol. Endocrinol. 8:693-703(1994). RN [9] RP PROTEIN SEQUENCE OF 170-180. RC TISSUE=Liver; RA Hochstrasser D.F., Frutiger S., Paquet N., Bairoch A., Ravier F., RA Pasquali C., Sanchez J.-C., Tissot J.-D., Bjellqvist B., Vargas R., RA Appel R.D., Hughes G.J.; RL Submitted (JUN-1992) to UniProtKB. RN [10] RP PROTEIN SEQUENCE OF 154-162 AND 169-180, SUBUNIT, AND TISSUE SPECIFICITY. RX PubMed=1426530; DOI=10.1016/0020-711x(92)90076-d; RA Kobayashi T., Honke K., Gasa S., Fujii T., Maguchi S., Miyazaki T., RA Makita A.; RT "Proteolytic processing sites producing the mature form of human cathepsin RT D."; RL Int. J. Biochem. 24:1487-1491(1992). RN [11] RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS]. RC TISSUE=Melanoma; RX PubMed=12643545; DOI=10.1021/pr025562r; RA Basrur V., Yang F., Kushimoto T., Higashimoto Y., Yasumoto K., Valencia J., RA Muller J., Vieira W.D., Watabe H., Shabanowitz J., Hearing V.J., Hunt D.F., RA Appella E.; RT "Proteomic analysis of early melanosomes: identification of novel RT melanosomal proteins."; RL J. Proteome Res. 2:69-79(2003). RN [12] RP GLYCOSYLATION AT ASN-263. RX PubMed=12754519; DOI=10.1038/nbt827; RA Zhang H., Li X.-J., Martin D.B., Aebersold R.; RT "Identification and quantification of N-linked glycoproteins using RT hydrazide chemistry, stable isotope labeling and mass spectrometry."; RL Nat. Biotechnol. 21:660-666(2003). RN [13] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-263. RC TISSUE=Plasma; RX PubMed=16335952; DOI=10.1021/pr0502065; RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J., RA Smith R.D.; RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction, RT hydrazide chemistry, and mass spectrometry."; RL J. Proteome Res. 4:2070-2080(2005). RN [14] RP INVOLVEMENT IN CLN10, AND VARIANT ARG-282. RX PubMed=16670177; DOI=10.1093/brain/awl107; RA Siintola E., Partanen S., Stromme P., Haapanen A., Haltia M., Maehlen J., RA Lehesjoki A.E., Tyynela J.; RT "Cathepsin D deficiency underlies congenital human neuronal ceroid- RT lipofuscinosis."; RL Brain 129:1438-1445(2006). RN [15] RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS]. RC TISSUE=Melanoma; RX PubMed=17081065; DOI=10.1021/pr060363j; RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H., Mangini N.J., RA Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R., Yamagishi S., RA Shabanowitz J., Hearing V.J., Wu C., Appella E., Hunt D.F.; RT "Proteomic and bioinformatic characterization of the biogenesis and RT function of melanosomes."; RL J. Proteome Res. 5:3135-3144(2006). RN [16] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-263. RC TISSUE=Platelet; RX PubMed=16263699; DOI=10.1074/mcp.m500324-mcp200; RA Lewandrowski U., Moebius J., Walter U., Sickmann A.; RT "Elucidation of N-glycosylation sites on human platelet proteins: a RT glycoproteomic approach."; RL Mol. Cell. Proteomics 5:226-233(2006). RN [17] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-134 AND ASN-263. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [18] RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=20551380; DOI=10.1074/mcp.m110.001693; RA Didangelos A., Yin X., Mandal K., Baumert M., Jahangiri M., Mayr M.; RT "Proteomics characterization of extracellular space components in the human RT aorta."; RL Mol. Cell. Proteomics 9:2048-2062(2010). RN [19] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [20] RP GLYCOSYLATION AT THR-63, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=23234360; DOI=10.1021/pr300963h; RA Halim A., Ruetschi U., Larson G., Nilsson J.; RT "LC-MS/MS characterization of O-glycosylation sites and glycan structures RT of human cerebrospinal fluid glycoproteins."; RL J. Proteome Res. 12:573-584(2013). RN [21] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [22] RP INTERACTION WITH ADAM30, IDENTIFICATION BY MASS SPECTROMETRY, AND CLEAVAGE. RX PubMed=27333034; DOI=10.1016/j.ebiom.2016.06.002; RA Letronne F., Laumet G., Ayral A.M., Chapuis J., Demiautte F., Laga M., RA Vandenberghe M.E., Malmanche N., Leroux F., Eysert F., Sottejeau Y., RA Chami L., Flaig A., Bauer C., Dourlen P., Lesaffre M., Delay C., Huot L., RA Dumont J., Werkmeister E., Lafont F., Mendes T., Hansmannel F., Dermaut B., RA Deprez B., Herard A.S., Dhenain M., Souedet N., Pasquier F., Tulasne D., RA Berr C., Hauw J.J., Lemoine Y., Amouyel P., Mann D., Deprez R., Checler F., RA Hot D., Delzescaux T., Gevaert K., Lambert J.C.; RT "ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in RT Alzheimer's Disease."; RL EBioMedicine 9:278-292(2016). RN [23] RP X-RAY CRYSTALLOGRAPHY (3 ANGSTROMS). RC TISSUE=Spleen; RX PubMed=8467789; DOI=10.1002/j.1460-2075.1993.tb05774.x; RA Metcalf P., Fusek M.; RT "Two crystal structures for cathepsin D: the lysosomal targeting signal and RT active site."; RL EMBO J. 12:1293-1302(1993). RN [24] RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS), AND SUBUNIT. RC TISSUE=Liver; RX PubMed=8393577; DOI=10.1073/pnas.90.14.6796; RA Baldwin E.T., Bhat T.N., Gulnik S., Hosur M.V., Sowder R.C. II, RA Cachau R.E., Collins J., Silva A.M., Erickson J.W.; RT "Crystal structures of native and inhibited forms of human cathepsin D: RT implications for lysosomal targeting and drug design."; RL Proc. Natl. Acad. Sci. U.S.A. 90:6796-6800(1993). RN [25] RP VARIANT VAL-58. RX PubMed=10716266; RX DOI=10.1002/1531-8249(200003)47:3<399::aid-ana22>3.3.co;2-x; RA Papassotiropoulos A., Bagli M., Kurz A., Kornhuber J., Forstl H., Maier W., RA Pauls J., Lautenschlager N., Heun R.; RT "A genetic variation of cathepsin D is a major risk factor for Alzheimer's RT disease."; RL Ann. Neurol. 47:399-403(2000). RN [26] RP VARIANTS CLN10 ILE-229 AND CYS-383. RX PubMed=16685649; DOI=10.1086/504159; RA Steinfeld R., Reinhardt K., Schreiber K., Hillebrand M., Kraetzner R., RA Bruck W., Saftig P., Gartner J.; RT "Cathepsin D deficiency is associated with a human neurodegenerative RT disorder."; RL Am. J. Hum. Genet. 78:988-998(2006). RN [27] RP VARIANT CLN10 ILE-229. RX PubMed=21990111; DOI=10.1002/humu.21624; RA Kousi M., Lehesjoki A.E., Mole S.E.; RT "Update of the mutation spectrum and clinical correlations of over 360 RT mutations in eight genes that underlie the neuronal ceroid RT lipofuscinoses."; RL Hum. Mutat. 33:42-63(2012). CC -!- FUNCTION: Acid protease active in intracellular protein breakdown. CC Plays a role in APP processing following cleavage and activation by CC ADAM30 which leads to APP degradation (PubMed:27333034). Involved in CC the pathogenesis of several diseases such as breast cancer and possibly CC Alzheimer disease. {ECO:0000269|PubMed:27333034}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Specificity similar to, but narrower than, that of pepsin A. CC Does not cleave the 4-Gln-|-His-5 bond in B chain of insulin.; CC EC=3.4.23.5; CC -!- SUBUNIT: Consists of a light chain and a heavy chain (PubMed:1426530, CC PubMed:8393577). Interacts with ADAM30; this leads to activation of CC CTSD (PubMed:27333034). Interacts with GRN; stabilizes CTSD; increases CC its proteolytic activity (By similarity). CC {ECO:0000250|UniProtKB:P18242, ECO:0000269|PubMed:1426530, CC ECO:0000269|PubMed:27333034, ECO:0000269|PubMed:8393577}. CC -!- INTERACTION: CC P07339; P05067: APP; NbExp=2; IntAct=EBI-2115097, EBI-77613; CC P07339; Q9P1A6-3: DLGAP2; NbExp=3; IntAct=EBI-2115097, EBI-12019838; CC P07339; I6L9I8: EPN3; NbExp=3; IntAct=EBI-2115097, EBI-12866582; CC P07339; Q9H6S3: EPS8L2; NbExp=3; IntAct=EBI-2115097, EBI-3940939; CC P07339; Q7Z602: GPR141; NbExp=3; IntAct=EBI-2115097, EBI-21649723; CC P07339; P28799: GRN; NbExp=4; IntAct=EBI-2115097, EBI-747754; CC P07339; PRO_0000012695 [P28799]: GRN; NbExp=2; IntAct=EBI-2115097, EBI-21335602; CC P07339; PRO_0000012696 [P28799]: GRN; NbExp=2; IntAct=EBI-2115097, EBI-21335615; CC P07339; PRO_0000012697 [P28799]: GRN; NbExp=2; IntAct=EBI-2115097, EBI-21335629; CC P07339; PRO_0000012698 [P28799]: GRN; NbExp=2; IntAct=EBI-2115097, EBI-21335642; CC P07339; PRO_0000012699 [P28799]: GRN; NbExp=2; IntAct=EBI-2115097, EBI-21335656; CC P07339; PRO_0000012700 [P28799]: GRN; NbExp=2; IntAct=EBI-2115097, EBI-21335669; CC P07339; PRO_0000012701 [P28799]: GRN; NbExp=2; IntAct=EBI-2115097, EBI-21335682; CC P07339; P68431: H3C12; NbExp=3; IntAct=EBI-2115097, EBI-79722; CC P07339; Q9Y6F6-3: IRAG1; NbExp=3; IntAct=EBI-2115097, EBI-25840037; CC P07339; Q12756: KIF1A; NbExp=3; IntAct=EBI-2115097, EBI-2679809; CC P07339; Q5TA79: LCE2A; NbExp=3; IntAct=EBI-2115097, EBI-10246607; CC P07339; Q86VF5-3: MOGAT3; NbExp=3; IntAct=EBI-2115097, EBI-25840143; CC P07339; O15130-2: NPFF; NbExp=3; IntAct=EBI-2115097, EBI-25840002; CC P07339; Q96LB9: PGLYRP3; NbExp=3; IntAct=EBI-2115097, EBI-12339509; CC P07339; P09565: PP9974; NbExp=3; IntAct=EBI-2115097, EBI-10196507; CC P07339; Q9C004: SPRY4; NbExp=3; IntAct=EBI-2115097, EBI-354861; CC P07339; Q8NBJ7: SUMF2; NbExp=3; IntAct=EBI-2115097, EBI-723091; CC P07339; Q9BQG1: SYT3; NbExp=3; IntAct=EBI-2115097, EBI-17284568; CC P07339; P28347-2: TEAD1; NbExp=3; IntAct=EBI-2115097, EBI-12151837; CC P07339; P45880: VDAC2; NbExp=3; IntAct=EBI-2115097, EBI-354022; CC P07339; Q15007-2: WTAP; NbExp=3; IntAct=EBI-2115097, EBI-25840023; CC P07339; O00308: WWP2; NbExp=3; IntAct=EBI-2115097, EBI-743923; CC P07339; Q5W0Z9-4: ZDHHC20; NbExp=3; IntAct=EBI-2115097, EBI-25840130; CC P07339; Q6ZNH5: ZNF497; NbExp=4; IntAct=EBI-2115097, EBI-10486136; CC -!- SUBCELLULAR LOCATION: Lysosome. Melanosome. Secreted, extracellular CC space. Note=Identified by mass spectrometry in melanosome fractions CC from stage I to stage IV. In aortic samples, detected as an CC extracellular protein loosely bound to the matrix (PubMed:20551380). CC {ECO:0000269|PubMed:20551380}. CC -!- TISSUE SPECIFICITY: Expressed in the aorta extracellular space (at CC protein level) (PubMed:20551380). Expressed in liver (at protein level) CC (PubMed:1426530). {ECO:0000269|PubMed:1426530, CC ECO:0000269|PubMed:20551380}. CC -!- PTM: N- and O-glycosylated. {ECO:0000269|PubMed:12754519, CC ECO:0000269|PubMed:16263699, ECO:0000269|PubMed:16335952, CC ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:23234360}. CC -!- PTM: Undergoes proteolytic cleavage and activation by ADAM30. CC {ECO:0000269|PubMed:27333034}. CC -!- PTM: As well as the major heavy chain which starts at Leu-169, 2 minor CC forms starting at Gly-170 and Gly-171 have been identified CC (PubMed:1426530). An additional form starting at Ala-168 has also been CC identified (PubMed:27333034). {ECO:0000269|PubMed:1426530, CC ECO:0000269|PubMed:27333034}. CC -!- POLYMORPHISM: The Val-58 allele is significantly overrepresented in CC demented patients (11.8%) compared with non-demented controls (4.9%). CC Carriers of the Val-58 allele have a 3.1-fold increased risk for CC developing AD than non-carriers. CC -!- DISEASE: Ceroid lipofuscinosis, neuronal, 10 (CLN10) [MIM:610127]: A CC form of neuronal ceroid lipofuscinosis with onset at birth or early CC childhood. Neuronal ceroid lipofuscinoses are progressive CC neurodegenerative, lysosomal storage diseases characterized by CC intracellular accumulation of autofluorescent liposomal material, and CC clinically by seizures, dementia, visual loss, and/or cerebral atrophy. CC {ECO:0000269|PubMed:16670177, ECO:0000269|PubMed:16685649, CC ECO:0000269|PubMed:21990111}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the peptidase A1 family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=NCL CTSD; Note=Neural Ceroid Lipofuscinoses mutation CC db; CC URL="https://www.ucl.ac.uk/ncl-disease/ncl-resource-gateway-batten-disease"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M11233; AAB59529.1; -; mRNA. DR EMBL; X05344; CAA28955.1; -; mRNA. DR EMBL; M63138; AAA51922.1; -; Genomic_DNA. DR EMBL; M63134; AAA51922.1; JOINED; Genomic_DNA. DR EMBL; M63135; AAA51922.1; JOINED; Genomic_DNA. DR EMBL; M63136; AAA51922.1; JOINED; Genomic_DNA. DR EMBL; M63137; AAA51922.1; JOINED; Genomic_DNA. DR EMBL; CR456947; CAG33228.1; -; mRNA. DR EMBL; BT006910; AAP35556.1; -; mRNA. DR EMBL; BT020155; AAV38957.1; -; mRNA. DR EMBL; BC016320; AAH16320.1; -; mRNA. DR EMBL; L12980; AAA16314.1; -; Genomic_DNA. DR EMBL; S74689; AAD14156.1; -; Genomic_DNA. DR EMBL; S52557; AAD13868.1; -; Genomic_DNA. DR CCDS; CCDS7725.1; -. DR PIR; A25771; KHHUD. DR RefSeq; NP_001900.1; NM_001909.5. DR PDB; 1LYA; X-ray; 2.50 A; A/C=65-161, B/D=170-410. DR PDB; 1LYB; X-ray; 2.50 A; A/C=65-161, B/D=170-410. DR PDB; 1LYW; X-ray; 2.50 A; A/C/E/G=65-161, B/D/F/H=170-410. DR PDB; 4OBZ; X-ray; 2.90 A; A/C=60-162, B/D=170-412. DR PDB; 4OC6; X-ray; 2.64 A; A=60-162, B=170-412. DR PDB; 4OD9; X-ray; 1.90 A; A/C=60-162, B/D=170-412. DR PDB; 6QBG; X-ray; 1.80 A; A=65-162, B=171-411. DR PDB; 6QBH; X-ray; 1.85 A; A=65-161, B=171-411. DR PDB; 6QCB; X-ray; 1.55 A; A=65-161, B=171-411. DR PDBsum; 1LYA; -. DR PDBsum; 1LYB; -. DR PDBsum; 1LYW; -. DR PDBsum; 4OBZ; -. DR PDBsum; 4OC6; -. DR PDBsum; 4OD9; -. DR PDBsum; 6QBG; -. DR PDBsum; 6QBH; -. DR PDBsum; 6QCB; -. DR AlphaFoldDB; P07339; -. DR SMR; P07339; -. DR BioGRID; 107889; 174. DR DIP; DIP-43906N; -. DR FunCoup; P07339; 1372. DR IntAct; P07339; 84. DR MINT; P07339; -. DR STRING; 9606.ENSP00000236671; -. DR BindingDB; P07339; -. DR ChEMBL; CHEMBL2581; -. DR DrugBank; DB03028; 1h-Benoximidazole-2-Carboxylic Acid. DR DrugBank; DB03096; 2-Morpholinoethylamine. DR DrugBank; DB07542; 5-Amino-6-cyclohexyl-4-hydroxy-2-isobutyl-hexanoic acid. DR DrugBank; DB08740; CYCLOHEXYLMETHYL-2,3-DIHYDROXY-5-METHYL-HEXYLAMIDE. DR DrugBank; DB02216; S-Methylcysteine. DR DrugCentral; P07339; -. DR GuidetoPHARMACOLOGY; 2345; -. DR MEROPS; A01.009; -. DR GlyConnect; 1079; 44 N-Linked glycans (2 sites). DR GlyCosmos; P07339; 3 sites, 44 glycans. DR GlyGen; P07339; 12 sites, 113 N-linked glycans (2 sites), 1 N-linked;o-linked glycan (1 site), 3 O-linked glycans (8 sites). DR iPTMnet; P07339; -. DR MetOSite; P07339; -. DR PhosphoSitePlus; P07339; -. DR SwissPalm; P07339; -. DR BioMuta; CTSD; -. DR DMDM; 115717; -. DR REPRODUCTION-2DPAGE; IPI00011229; -. DR CPTAC; CPTAC-486; -. DR CPTAC; CPTAC-487; -. DR CPTAC; CPTAC-658; -. DR jPOST; P07339; -. DR MassIVE; P07339; -. DR PaxDb; 9606-ENSP00000236671; -. DR PeptideAtlas; P07339; -. DR ProteomicsDB; 51994; -. DR Pumba; P07339; -. DR TopDownProteomics; P07339; -. DR Antibodypedia; 880; 1183 antibodies from 47 providers. DR DNASU; 1509; -. DR Ensembl; ENST00000236671.7; ENSP00000236671.2; ENSG00000117984.16. DR GeneID; 1509; -. DR KEGG; hsa:1509; -. DR MANE-Select; ENST00000236671.7; ENSP00000236671.2; NM_001909.5; NP_001900.1. DR AGR; HGNC:2529; -. DR ClinPGx; PA27029; -. DR CTD; 1509; -. DR DisGeNET; 1509; -. DR GeneCards; CTSD; -. DR GeneReviews; CTSD; -. DR HGNC; HGNC:2529; CTSD. DR HPA; ENSG00000117984; Low tissue specificity. DR MalaCards; CTSD; -. DR MIM; 116840; gene. DR MIM; 610127; phenotype. DR OpenTargets; ENSG00000117984; -. DR Orphanet; 700487; Congenital CLN10 disease. DR Orphanet; 700497; Juvenile CLN10 disease. DR Orphanet; 700492; Late infantile CLN10 disease. DR VEuPathDB; HostDB:ENSG00000117984; -. DR eggNOG; KOG1339; Eukaryota. DR GeneTree; ENSGT00940000155733; -. DR HOGENOM; CLU_013253_3_3_1; -. DR InParanoid; P07339; -. DR OMA; KYDHDAS; -. DR OrthoDB; 771136at2759; -. DR PAN-GO; P07339; 4 GO annotations based on evolutionary models. DR PhylomeDB; P07339; -. DR BioCyc; MetaCyc:HS04183-MONOMER; -. DR BRENDA; 3.4.23.5; 2681. DR PathwayCommons; P07339; -. DR Reactome; R-HSA-1442490; Collagen degradation. DR Reactome; R-HSA-2022377; Metabolism of Angiotensinogen to Angiotensins. DR Reactome; R-HSA-2132295; MHC class II antigen presentation. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR Reactome; R-HSA-77387; Insulin receptor recycling. DR Reactome; R-HSA-9018519; Estrogen-dependent gene expression. DR SignaLink; P07339; -. DR SIGNOR; P07339; -. DR Agora; ENSG00000117984; -. DR BioGRID-ORCS; 1509; 9 hits in 1161 CRISPR screens. DR ChiTaRS; CTSD; human. DR EvolutionaryTrace; P07339; -. DR GeneWiki; Cathepsin_D; -. DR GenomeRNAi; 1509; -. DR Pharos; P07339; Tchem. DR PRO; PR:P07339; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; P07339; protein. DR Bgee; ENSG00000117984; Expressed in right adrenal gland cortex and 199 other cell types or tissues. DR ExpressionAtlas; P07339; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:ARUK-UCL. DR GO; GO:0031904; C:endosome lumen; IEA:Ensembl. DR GO; GO:0010008; C:endosome membrane; IDA:ARUK-UCL. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0031012; C:extracellular matrix; HDA:BHF-UCL. DR GO; GO:0005576; C:extracellular region; HDA:BHF-UCL. DR GO; GO:0005615; C:extracellular space; HDA:UniProtKB. DR GO; GO:1904813; C:ficolin-1-rich granule lumen; TAS:Reactome. DR GO; GO:0043202; C:lysosomal lumen; TAS:Reactome. DR GO; GO:0005765; C:lysosomal membrane; IDA:ARUK-UCL. DR GO; GO:0005764; C:lysosome; IDA:UniProtKB. DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell. DR GO; GO:0045121; C:membrane raft; IDA:UniProtKB. DR GO; GO:0035580; C:specific granule lumen; TAS:Reactome. DR GO; GO:1904724; C:tertiary granule lumen; TAS:Reactome. DR GO; GO:0004190; F:aspartic-type endopeptidase activity; IBA:GO_Central. DR GO; GO:0070001; F:aspartic-type peptidase activity; ISS:ARUK-UCL. DR GO; GO:0004197; F:cysteine-type endopeptidase activity; TAS:Reactome. DR GO; GO:0008233; F:peptidase activity; IDA:ARUK-UCL. DR GO; GO:0019886; P:antigen processing and presentation of exogenous peptide antigen via MHC class II; TAS:Reactome. DR GO; GO:0000045; P:autophagosome assembly; IEA:Ensembl. DR GO; GO:0097194; P:execution phase of apoptosis; IDA:ARUK-UCL. DR GO; GO:1901143; P:insulin catabolic process; IEA:Ensembl. DR GO; GO:0038020; P:insulin receptor recycling; IEA:Ensembl. DR GO; GO:0042159; P:lipoprotein catabolic process; IDA:ARUK-UCL. DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:ARUK-UCL. DR GO; GO:0006508; P:proteolysis; IDA:ARUK-UCL. DR GO; GO:0070201; P:regulation of establishment of protein localization; IDA:ARUK-UCL. DR CDD; cd05490; Cathepsin_D2; 1. DR FunFam; 2.40.70.10:FF:000039; Cathepsin D preproprotein; 1. DR FunFam; 2.40.70.10:FF:000047; Cathepsin D preproprotein; 1. DR Gene3D; 2.40.70.10; Acid Proteases; 2. DR InterPro; IPR001461; Aspartic_peptidase_A1. DR InterPro; IPR001969; Aspartic_peptidase_AS. DR InterPro; IPR012848; Aspartic_peptidase_N. DR InterPro; IPR033144; Cathepsin_D. DR InterPro; IPR033121; PEPTIDASE_A1. DR InterPro; IPR021109; Peptidase_aspartic_dom_sf. DR PANTHER; PTHR47966; BETA-SITE APP-CLEAVING ENZYME, ISOFORM A-RELATED; 1. DR PANTHER; PTHR47966:SF42; CATHEPSIN D; 1. DR Pfam; PF07966; A1_Propeptide; 1. DR Pfam; PF00026; Asp; 1. DR PRINTS; PR00792; PEPSIN. DR SUPFAM; SSF50630; Acid proteases; 1. DR PROSITE; PS00141; ASP_PROTEASE; 2. DR PROSITE; PS51767; PEPTIDASE_A1; 1. PE 1: Evidence at protein level; KW 3D-structure; Alzheimer disease; Aspartyl protease; KW Direct protein sequencing; Disease variant; Disulfide bond; Glycoprotein; KW Hydrolase; Lysosome; Neurodegeneration; Neuronal ceroid lipofuscinosis; KW Protease; Proteomics identification; Reference proteome; Secreted; Signal; KW Zymogen. FT SIGNAL 1..20 FT /evidence="ECO:0000255" FT PROPEP 21..64 FT /note="Activation peptide" FT /id="PRO_0000025949" FT CHAIN 65..412 FT /note="Cathepsin D" FT /id="PRO_0000025950" FT CHAIN 65..162 FT /note="Cathepsin D light chain" FT /evidence="ECO:0000305|PubMed:1426530" FT /id="PRO_0000025951" FT CHAIN 169..412 FT /note="Cathepsin D heavy chain" FT /evidence="ECO:0000305|PubMed:1426530" FT /id="PRO_0000025952" FT DOMAIN 79..407 FT /note="Peptidase A1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01103" FT ACT_SITE 97 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10094, FT ECO:0000269|PubMed:8393577" FT ACT_SITE 295 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10094, FT ECO:0000269|PubMed:8393577" FT CARBOHYD 63 FT /note="O-linked (GalNAc...) threonine" FT /evidence="ECO:0000269|PubMed:23234360" FT CARBOHYD 134 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218" FT CARBOHYD 263 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:12754519, FT ECO:0000269|PubMed:16263699, ECO:0000269|PubMed:16335952, FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:8393577" FT DISULFID 91..160 FT /evidence="ECO:0000269|PubMed:8393577" FT DISULFID 110..117 FT /evidence="ECO:0000269|PubMed:8393577" FT DISULFID 286..290 FT /evidence="ECO:0000269|PubMed:8393577" FT DISULFID 329..366 FT VARIANT 58 FT /note="A -> V (associated with increased risk for AD; FT possibly influences secretion and intracellular maturation; FT dbSNP:rs17571)" FT /evidence="ECO:0000269|PubMed:10716266" FT /id="VAR_011621" FT VARIANT 229 FT /note="F -> I (in CLN10; dbSNP:rs121912789)" FT /evidence="ECO:0000269|PubMed:16685649, FT ECO:0000269|PubMed:21990111" FT /id="VAR_029362" FT VARIANT 282 FT /note="G -> R (in dbSNP:rs147278302)" FT /evidence="ECO:0000269|PubMed:16670177" FT /id="VAR_058490" FT VARIANT 383 FT /note="W -> C (in CLN10; dbSNP:rs121912790)" FT /evidence="ECO:0000269|PubMed:16685649" FT /id="VAR_029363" FT STRAND 67..74 FT /evidence="ECO:0007829|PDB:4OD9" FT TURN 75..77 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 78..85 FT /evidence="ECO:0007829|PDB:4OD9" FT TURN 86..89 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 90..97 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 103..107 FT /evidence="ECO:0007829|PDB:4OD9" FT HELIX 115..118 FT /evidence="ECO:0007829|PDB:4OD9" FT HELIX 125..127 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 132..141 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 146..159 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 172..184 FT /evidence="ECO:0007829|PDB:4OD9" FT HELIX 189..192 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 194..200 FT /evidence="ECO:0007829|PDB:4OD9" FT HELIX 204..206 FT /evidence="ECO:0007829|PDB:4OD9" FT HELIX 208..210 FT /evidence="ECO:0007829|PDB:4OD9" FT HELIX 214..220 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 224..226 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 228..233 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 236..238 FT /evidence="ECO:0007829|PDB:1LYW" FT STRAND 239..249 FT /evidence="ECO:0007829|PDB:4OD9" FT HELIX 252..254 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 255..263 FT /evidence="ECO:0007829|PDB:4OD9" FT TURN 267..270 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 271..274 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 276..279 FT /evidence="ECO:0007829|PDB:4OD9" FT TURN 280..282 FT /evidence="ECO:0007829|PDB:1LYW" FT STRAND 284..286 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 290..294 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 299..303 FT /evidence="ECO:0007829|PDB:4OD9" FT HELIX 305..314 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 318..321 FT /evidence="ECO:0007829|PDB:1LYA" FT STRAND 325..327 FT /evidence="ECO:0007829|PDB:4OD9" FT HELIX 329..334 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 338..342 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 345..349 FT /evidence="ECO:0007829|PDB:4OD9" FT HELIX 351..354 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 355..360 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 363..372 FT /evidence="ECO:0007829|PDB:4OD9" FT TURN 377..379 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 383..385 FT /evidence="ECO:0007829|PDB:4OD9" FT HELIX 387..392 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 393..398 FT /evidence="ECO:0007829|PDB:4OD9" FT TURN 399..402 FT /evidence="ECO:0007829|PDB:4OD9" FT STRAND 403..409 FT /evidence="ECO:0007829|PDB:4OD9" SQ SEQUENCE 412 AA; 44552 MW; 903FB8412E0CF0B0 CRC64; MQPSSLLPLA LCLLAAPASA LVRIPLHKFT SIRRTMSEVG GSVEDLIAKG PVSKYSQAVP AVTEGPIPEV LKNYMDAQYY GEIGIGTPPQ CFTVVFDTGS SNLWVPSIHC KLLDIACWIH HKYNSDKSST YVKNGTSFDI HYGSGSLSGY LSQDTVSVPC QSASSASALG GVKVERQVFG EATKQPGITF IAAKFDGILG MAYPRISVNN VLPVFDNLMQ QKLVDQNIFS FYLSRDPDAQ PGGELMLGGT DSKYYKGSLS YLNVTRKAYW QVHLDQVEVA SGLTLCKEGC EAIVDTGTSL MVGPVDEVRE LQKAIGAVPL IQGEYMIPCE KVSTLPAITL KLGGKGYKLS PEDYTLKVSQ AGKTLCLSGF MGMDIPPPSG PLWILGDVFI GRYYTVFDRD NNRVGFAEAA RL // ID CSEN_HUMAN Reviewed; 256 AA. AC Q9Y2W7; H7BY46; Q3YAC3; Q3YAC4; Q53TJ5; Q96T40; Q9UJ84; Q9UJ85; DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1999, sequence version 1. DT 28-JAN-2026, entry version 209. DE RecName: Full=Calsenilin; DE AltName: Full=A-type potassium channel modulatory protein 3; DE AltName: Full=DRE-antagonist modulator; DE Short=DREAM; DE AltName: Full=Kv channel-interacting protein 3; DE Short=KChIP3; GN Name=KCNIP3; Synonyms=CSEN, DREAM, KCHIP3; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION IN PRESENILIN RP REGULATION. RX PubMed=9771752; DOI=10.1038/2673; RA Buxbaum J.D., Choi E.K., Luo Y., Lilliehook C., Crowley A.C., Merriam D.E., RA Wasco W.; RT "Calsenilin: a calcium-binding protein that interacts with the presenilins RT and regulates the levels of a presenilin fragment."; RL Nat. Med. 4:1177-1181(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION IN TRANSCRIPTION RP REGULATION. RC TISSUE=Caudate nucleus; RX PubMed=10078534; DOI=10.1038/18044; RA Carrion A.M., Link W.A., Ledo F., Mellstrom B., Naranjo J.R.; RT "DREAM is a Ca2+-regulated transcriptional repressor."; RL Nature 398:80-84(1999). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION IN POTASSIUM RP TRANSPORT. RX PubMed=10676964; DOI=10.1038/35000592; RA An W.F., Bowlby M.R., Betty M., Cao J., Ling H.-P., Mendoza G., RA Hinson J.W., Mattsson K.I., Strassle B.W., Trimmer J.S., Rhodes K.J.; RT "Modulation of A-type potassium channels by a family of calcium sensors."; RL Nature 403:553-556(2000). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 3), AND ALTERNATIVE SPLICING. RX PubMed=16112838; DOI=10.1016/j.ygeno.2005.07.001; RA Pruunsild P., Timmusk T.; RT "Structure, alternative splicing, and expression of the human and mouse RT KCNIP gene family."; RL Genomics 86:581-593(2005). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RA Isbrandt D., Pongs O.; RL Submitted (MAR-2001) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [11] RP INTERACTION WITH PSEN2, SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, AND RP MUTAGENESIS OF ASP-61 AND ASP-64. RX PubMed=11278424; DOI=10.1074/jbc.m008597200; RA Choi E.K., Zaidi N.F., Miller J.S., Crowley A.C., Merriam D.E., RA Lilliehook C., Buxbaum J.D., Wasco W.; RT "Calsenilin is a substrate for caspase-3 that preferentially interacts with RT the familial Alzheimer's disease-associated C-terminal fragment of RT presenilin 2."; RL J. Biol. Chem. 276:19197-19204(2001). RN [12] RP FUNCTION IN APOPTOSIS. RX PubMed=11259376; DOI=10.1096/fj.00-0541fje; RA Jo D.G., Kim M.J., Choi Y.H., Kim I.K., Song Y.H., Woo H.N., Chung C.W., RA Jung Y.K.; RT "Pro-apoptotic function of calsenilin/DREAM/KChIP3."; RL FASEB J. 15:589-591(2001). RN [13] RP FUNCTION IN APOPTOSIS. RX PubMed=11988022; DOI=10.1006/mcne.2001.1096; RA Lilliehook C., Chan S., Choi E.K., Zaidi N.F., Wasco W., Mattson M.P., RA Buxbaum J.D.; RT "Calsenilin enhances apoptosis by altering endoplasmic reticulum calcium RT signaling."; RL Mol. Cell. Neurosci. 19:552-559(2002). RN [14] RP FUNCTION IN POTASSIUM TRANSPORT. RX PubMed=12829703; DOI=10.1074/jbc.m306142200; RA Shibata R., Misonou H., Campomanes C.R., Anderson A.E., Schrader L.A., RA Doliveira L.C., Carroll K.I., Sweatt J.D., Rhodes K.J., Trimmer J.S.; RT "A fundamental role for KChIPs in determining the molecular properties and RT trafficking of Kv4.2 potassium channels."; RL J. Biol. Chem. 278:36445-36454(2003). RN [15] RP PHOSPHORYLATION AT SER-63. RX PubMed=12837631; DOI=10.1016/s1044-7431(03)00072-1; RA Choi E.K., Miller J.S., Zaidi N.F., Salih E., Buxbaum J.D., Wasco W.; RT "Phosphorylation of calsenilin at Ser63 regulates its cleavage by caspase- RT 3."; RL Mol. Cell. Neurosci. 23:495-506(2003). RN [16] RP INTERACTION WITH KCND2, FUNCTION IN POTASSIUM TRANSPORT, SUBUNIT, AND RP SUBCELLULAR LOCATION. RX PubMed=15485870; DOI=10.1074/jbc.m409721200; RA Kunjilwar K., Strang C., DeRubeis D., Pfaffinger P.J.; RT "KChIP3 rescues the functional expression of Shal channel tetramerization RT mutants."; RL J. Biol. Chem. 279:54542-54551(2004). RN [17] RP TISSUE SPECIFICITY. RX PubMed=14720210; DOI=10.1111/j.1471-4159.2004.02159.x; RA Jo D.G., Lee J.Y., Hong Y.M., Song S., Mook-Jung I., Koh J.Y., Jung Y.K.; RT "Induction of pro-apoptotic calsenilin/DREAM/KChIP3 in Alzheimer's disease RT and cultured neurons after amyloid-beta exposure."; RL J. Neurochem. 88:604-611(2004). RN [18] RP FUNCTION IN POTASSIUM TRANSPORT. RX PubMed=16123112; DOI=10.1113/jphysiol.2005.087858; RA Jerng H.H., Kunjilwar K., Pfaffinger P.J.; RT "Multiprotein assembly of Kv4.2, KChIP3 and DPP10 produces ternary channel RT complexes with ISA-like properties."; RL J. Physiol. (Lond.) 568:767-788(2005). RN [19] RP FUNCTION IN POTASSIUM TRANSPORT, INTERACTION WITH KCND2, AND SUBCELLULAR RP LOCATION. RX PubMed=18957440; DOI=10.1074/jbc.m806852200; RA Jerng H.H., Pfaffinger P.J.; RT "Multiple Kv channel-interacting proteins contain an N-terminal RT transmembrane domain that regulates Kv4 channel trafficking and gating."; RL J. Biol. Chem. 283:36046-36059(2008). RN [20] RP SUMOYLATION AT LYS-26 AND LYS-90, AND SUBCELLULAR LOCATION. RX PubMed=21070824; DOI=10.1016/j.bbamcr.2010.11.001; RA Palczewska M., Casafont I., Ghimire K., Rojas A.M., Valencia A., RA Lafarga M., Mellstrom B., Naranjo J.R.; RT "Sumoylation regulates nuclear localization of repressor DREAM."; RL Biochim. Biophys. Acta 1813:1050-1058(2011). RN [21] RP STRUCTURE BY NMR OF 161-256, SUBUNIT, AND CALCIUM-BINDING. RX PubMed=17962406; DOI=10.1110/ps.072928007; RA Yu L., Sun C., Mendoza R., Wang J., Matayoshi E.D., Hebert E., RA Pereda-Lopez A., Hajduk P.J., Olejniczak E.T.; RT "Solution structure and calcium-binding properties of EF-hands 3 and 4 of RT calsenilin."; RL Protein Sci. 16:2502-2509(2007). RN [22] RP VARIANTS [LARGE SCALE ANALYSIS] SER-170 AND TYR-179. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). CC -!- FUNCTION: Calcium-dependent transcriptional repressor that binds to the CC DRE element of genes including PDYN and FOS. Affinity for DNA is CC reduced upon binding to calcium and enhanced by binding to magnesium. CC Seems to be involved in nociception (By similarity). CC {ECO:0000250|UniProtKB:Q9QXT8}. CC -!- FUNCTION: Regulatory subunit of Kv4/D (Shal)-type voltage-gated rapidly CC inactivating A-type potassium channels, such as KCND2/Kv4.2 and CC KCND3/Kv4.3. Modulates channel expression at the cell membrane, gating CC characteristics, inactivation kinetics and rate of recovery from CC inactivation in a calcium-dependent and isoform-specific manner. CC {ECO:0000269|PubMed:10676964, ECO:0000269|PubMed:12829703, CC ECO:0000269|PubMed:15485870, ECO:0000269|PubMed:16123112, CC ECO:0000269|PubMed:18957440}. CC -!- FUNCTION: May play a role in the regulation of PSEN2 proteolytic CC processing and apoptosis. Together with PSEN2 involved in modulation of CC amyloid-beta formation. {ECO:0000269|PubMed:11259376, CC ECO:0000269|PubMed:11988022, ECO:0000269|PubMed:9771752}. CC -!- SUBUNIT: Binds to DNA as a homomultimer. Dimerization is induced by CC binding to calcium (PubMed:17962406). Interacts with the C-terminus of CC PSEN1 and PSEN2 and with PSEN2 CTF subunit. Associates with KCN1. CC Component of heteromultimeric potassium channels. Identified in CC potassium channel complexes containing KCND1, KCND2, KCND3, KCNIP1, CC KCNIP2, KCNIP3, KCNIP4, DPP6 and DPP10 (By similarity). Interacts with CC KCND2 and KCND3. {ECO:0000250|UniProtKB:Q9QXT8, CC ECO:0000269|PubMed:11278424, ECO:0000269|PubMed:15485870, CC ECO:0000269|PubMed:17962406, ECO:0000269|PubMed:18957440}. CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:18957440}. Cell CC membrane {ECO:0000269|PubMed:15485870, ECO:0000269|PubMed:18957440}; CC Lipid-anchor {ECO:0000250}. Endoplasmic reticulum CC {ECO:0000269|PubMed:11278424, ECO:0000269|PubMed:18957440}. Golgi CC apparatus {ECO:0000269|PubMed:11278424}. Nucleus CC {ECO:0000269|PubMed:21070824}. Note=Also membrane-bound, associated CC with the plasma membrane (PubMed:15485870). In the presence of PSEN2 CC associated with the endoplasmic reticulum and Golgi. The sumoylated CC form is present only in the nucleus. {ECO:0000269|PubMed:11278424, CC ECO:0000269|PubMed:15485870, ECO:0000269|PubMed:21070824}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; Synonyms=KChIP3.1; CC IsoId=Q9Y2W7-1; Sequence=Displayed; CC Name=2; Synonyms=KChIP3.2, KChIP4.2; CC IsoId=Q9Y2W7-2; Sequence=VSP_015040; CC Name=3; Synonyms=KChip3.x; CC IsoId=Q9Y2W7-3; Sequence=VSP_040982, VSP_040983; CC -!- TISSUE SPECIFICITY: Highly expressed in brain. Widely expressed at CC lower levels. Expression levels are elevated in brain cortex regions CC affected by Alzheimer disease. {ECO:0000269|PubMed:14720210}. CC -!- PTM: Palmitoylated. Palmitoylation enhances association with the plasma CC membrane (By similarity). {ECO:0000250}. CC -!- PTM: Proteolytically cleaved by caspase-3. CC {ECO:0000269|PubMed:11278424}. CC -!- PTM: Phosphorylation at Ser-63 inhibits cleavage by CASP3. CC {ECO:0000269|PubMed:11278424, ECO:0000269|PubMed:12837631}. CC -!- SIMILARITY: Belongs to the recoverin family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF120102; AAD20350.1; -; mRNA. DR EMBL; AJ131730; CAB56836.1; -; mRNA. DR EMBL; AJ131730; CAB56835.1; -; mRNA. DR EMBL; AF199599; AAF33684.1; -; mRNA. DR EMBL; DQ148485; AAZ77802.1; -; mRNA. DR EMBL; DQ148486; AAZ77803.1; -; mRNA. DR EMBL; AF367022; AAK53711.1; -; mRNA. DR EMBL; BT020075; AAV38878.1; -; mRNA. DR EMBL; AK315437; BAG37825.1; -; mRNA. DR EMBL; AC009238; AAY14752.1; -; Genomic_DNA. DR EMBL; CH471219; EAX10724.1; -; Genomic_DNA. DR EMBL; BC012850; AAH12850.1; -; mRNA. DR CCDS; CCDS2013.1; -. [Q9Y2W7-1] DR CCDS; CCDS33245.1; -. [Q9Y2W7-3] DR RefSeq; NP_001030086.1; NM_001034914.2. [Q9Y2W7-3] DR RefSeq; NP_038462.1; NM_013434.5. [Q9Y2W7-1] DR PDB; 2E6W; NMR; -; A=161-256. DR PDBsum; 2E6W; -. DR AlphaFoldDB; Q9Y2W7; -. DR SMR; Q9Y2W7; -. DR BioGRID; 119042; 33. DR FunCoup; Q9Y2W7; 414. DR STRING; 9606.ENSP00000295225; -. DR TCDB; 8.A.82.2.5; the calmodulin calcium binding protein (calmodulin) family. DR iPTMnet; Q9Y2W7; -. DR PhosphoSitePlus; Q9Y2W7; -. DR BioMuta; KCNIP3; -. DR DMDM; 13431428; -. DR MassIVE; Q9Y2W7; -. DR PaxDb; 9606-ENSP00000295225; -. DR PeptideAtlas; Q9Y2W7; -. DR ProteomicsDB; 43500; -. DR ProteomicsDB; 85919; -. [Q9Y2W7-1] DR ProteomicsDB; 85920; -. [Q9Y2W7-2] DR ProteomicsDB; 85921; -. [Q9Y2W7-3] DR ABCD; Q9Y2W7; 2 sequenced antibodies. DR Antibodypedia; 4181; 544 antibodies from 40 providers. DR DNASU; 30818; -. DR Ensembl; ENST00000295225.10; ENSP00000295225.5; ENSG00000115041.15. [Q9Y2W7-1] DR Ensembl; ENST00000468529.1; ENSP00000417499.1; ENSG00000115041.15. [Q9Y2W7-3] DR GeneID; 30818; -. DR KEGG; hsa:30818; -. DR MANE-Select; ENST00000295225.10; ENSP00000295225.5; NM_013434.5; NP_038462.1. DR UCSC; uc002sup.4; human. [Q9Y2W7-1] DR AGR; HGNC:15523; -. DR ClinPGx; PA26934; -. DR CTD; 30818; -. DR DisGeNET; 30818; -. DR GeneCards; KCNIP3; -. DR HGNC; HGNC:15523; KCNIP3. DR HPA; ENSG00000115041; Tissue enhanced (brain, lymphoid tissue, parathyroid gland). DR MIM; 604662; gene. DR OpenTargets; ENSG00000115041; -. DR VEuPathDB; HostDB:ENSG00000115041; -. DR eggNOG; KOG0044; Eukaryota. DR GeneTree; ENSGT00940000158782; -. DR HOGENOM; CLU_072366_2_2_1; -. DR InParanoid; Q9Y2W7; -. DR OMA; TITKKEW; -. DR OrthoDB; 191686at2759; -. DR PAN-GO; Q9Y2W7; 8 GO annotations based on evolutionary models. DR PhylomeDB; Q9Y2W7; -. DR PathwayCommons; Q9Y2W7; -. DR Reactome; R-HSA-5576894; Phase 1 - inactivation of fast Na+ channels. DR Reactome; R-HSA-9768777; Regulation of NPAS4 gene transcription. DR SignaLink; Q9Y2W7; -. DR SIGNOR; Q9Y2W7; -. DR Agora; ENSG00000115041; -. DR BioGRID-ORCS; 30818; 22 hits in 1155 CRISPR screens. DR ChiTaRS; KCNIP3; human. DR EvolutionaryTrace; Q9Y2W7; -. DR GeneWiki; Calsenilin; -. DR GenomeRNAi; 30818; -. DR Pharos; Q9Y2W7; Tbio. DR PRO; PR:Q9Y2W7; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; Q9Y2W7; protein. DR Bgee; ENSG00000115041; Expressed in right frontal lobe and 110 other cell types or tissues. DR ExpressionAtlas; Q9Y2W7; baseline and differential. DR GO; GO:0005829; C:cytosol; ISS:UniProtKB. DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell. DR GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0008076; C:voltage-gated potassium channel complex; ISS:UniProtKB. DR GO; GO:0005509; F:calcium ion binding; IBA:GO_Central. DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:ARUK-UCL. DR GO; GO:0005267; F:potassium channel activity; IEA:UniProtKB-KW. DR GO; GO:0015459; F:potassium channel regulator activity; ISS:UniProtKB. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:ARUK-UCL. DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:ARUK-UCL. DR GO; GO:0072659; P:protein localization to plasma membrane; ISS:UniProtKB. DR GO; GO:1901379; P:regulation of potassium ion transmembrane transport; ISS:UniProtKB. DR GO; GO:0009966; P:regulation of signal transduction; IBA:GO_Central. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR CDD; cd00051; EFh; 2. DR FunFam; 1.10.238.10:FF:000043; Kv channel-interacting protein 1 isoform 2; 1. DR Gene3D; 1.10.238.10; EF-hand; 1. DR InterPro; IPR011992; EF-hand-dom_pair. DR InterPro; IPR018247; EF_Hand_1_Ca_BS. DR InterPro; IPR002048; EF_hand_dom. DR InterPro; IPR028846; Recoverin. DR PANTHER; PTHR23055; CALCIUM BINDING PROTEINS; 1. DR PANTHER; PTHR23055:SF165; CALSENILIN; 1. DR Pfam; PF13499; EF-hand_7; 1. DR Pfam; PF13833; EF-hand_8; 1. DR PRINTS; PR00450; RECOVERIN. DR SMART; SM00054; EFh; 3. DR SUPFAM; SSF47473; EF-hand; 1. DR PROSITE; PS00018; EF_HAND_1; 2. DR PROSITE; PS50222; EF_HAND_2; 3. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Apoptosis; Calcium; Cell membrane; KW Cytoplasm; Endoplasmic reticulum; Golgi apparatus; Ion channel; KW Ion transport; Isopeptide bond; Lipoprotein; Membrane; Metal-binding; KW Nucleus; Palmitate; Phosphoprotein; Potassium; Potassium channel; KW Potassium transport; Proteomics identification; Reference proteome; Repeat; KW Repressor; Transcription; Transcription regulation; Transport; KW Ubl conjugation; Voltage-gated channel. FT CHAIN 1..256 FT /note="Calsenilin" FT /id="PRO_0000073814" FT DOMAIN 67..123 FT /note="EF-hand 1; degenerate" FT /evidence="ECO:0000305" FT DOMAIN 126..161 FT /note="EF-hand 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448" FT DOMAIN 162..197 FT /note="EF-hand 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448" FT DOMAIN 210..245 FT /note="EF-hand 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448" FT REGION 1..20 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 243..256 FT /note="Interaction with KCND2" FT /evidence="ECO:0000250" FT BINDING 175 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448" FT BINDING 177 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448" FT BINDING 179 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448" FT BINDING 181 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448" FT BINDING 186 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448" FT BINDING 223 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448" FT BINDING 225 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448" FT BINDING 227 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448" FT BINDING 234 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448" FT MOD_RES 14 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9JM47" FT MOD_RES 60 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9QXT8" FT MOD_RES 63 FT /note="Phosphoserine; by CK1" FT /evidence="ECO:0000269|PubMed:12837631" FT LIPID 45 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000250" FT LIPID 46 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000250" FT CROSSLNK 26 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO1)" FT /evidence="ECO:0000269|PubMed:21070824" FT CROSSLNK 90 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO1)" FT /evidence="ECO:0000269|PubMed:21070824" FT VAR_SEQ 1..26 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:16112838" FT /id="VSP_040982" FT VAR_SEQ 27..60 FT /note="KEGIKWQRPRLSRQALMRCCLVKWILSSTAPQGS -> MGIQGMELCAMAVV FT VLLFIAVLKQFGILEPISME (in isoform 3)" FT /evidence="ECO:0000303|PubMed:16112838" FT /id="VSP_040983" FT VAR_SEQ 103..124 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|Ref.5" FT /id="VSP_015040" FT VARIANT 119 FT /note="A -> V (in dbSNP:rs35658670)" FT /id="VAR_048663" FT VARIANT 170 FT /note="A -> S (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_035463" FT VARIANT 179 FT /note="D -> Y (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_035464" FT MUTAGEN 61 FT /note="D->A: Abolishes cleavage by caspase-3." FT /evidence="ECO:0000269|PubMed:11278424" FT MUTAGEN 64 FT /note="D->A: Abolishes cleavage by caspase-3." FT /evidence="ECO:0000269|PubMed:11278424" FT CONFLICT 182 FT /note="I -> V (in Ref. 2; CAB56836/CAB56835)" FT /evidence="ECO:0000305" FT CONFLICT 207 FT /note="R -> Q (in Ref. 2; CAB56836/CAB56835)" FT /evidence="ECO:0000305" FT HELIX 164..174 FT /evidence="ECO:0007829|PDB:2E6W" FT STRAND 179..182 FT /evidence="ECO:0007829|PDB:2E6W" FT HELIX 184..193 FT /evidence="ECO:0007829|PDB:2E6W" FT STRAND 211..213 FT /evidence="ECO:0007829|PDB:2E6W" FT HELIX 214..222 FT /evidence="ECO:0007829|PDB:2E6W" FT STRAND 227..231 FT /evidence="ECO:0007829|PDB:2E6W" FT HELIX 232..239 FT /evidence="ECO:0007829|PDB:2E6W" FT HELIX 243..254 FT /evidence="ECO:0007829|PDB:2E6W" SQ SEQUENCE 256 AA; 29231 MW; 635C3EDF8B91E1C5 CRC64; MQPAKEVTKA SDGSLLGDLG HTPLSKKEGI KWQRPRLSRQ ALMRCCLVKW ILSSTAPQGS DSSDSELELS TVRHQPEGLD QLQAQTKFTK KELQSLYRGF KNECPTGLVD EDTFKLIYAQ FFPQGDATTY AHFLFNAFDA DGNGAIHFED FVVGLSILLR GTVHEKLKWA FNLYDINKDG YITKEEMLAI MKSIYDMMGR HTYPILREDA PAEHVERFFE KMDRNQDGVV TIEEFLEACQ KDENIMSSMQ LFENVI // ID DREB_HUMAN Reviewed; 649 AA. AC Q16643; A8MV58; B2RBG0; Q9UFZ5; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 25-NOV-2008, sequence version 4. DT 28-JAN-2026, entry version 224. DE RecName: Full=Drebrin; DE AltName: Full=Developmentally-regulated brain protein; GN Name=DBN1; Synonyms=D0S117E; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND VARIANTS RP VAL-446 AND PRO-553. RC TISSUE=Fetal brain; RX PubMed=8216329; DOI=10.1006/bbrc.1993.2273; RA Toda M., Shirao T., Minoshima S., Shimizu N., Toya S., Uyemura K.; RT "Molecular cloning of cDNA encoding human drebrin E and chromosomal mapping RT of its gene."; RL Biochem. Biophys. Res. Commun. 196:468-472(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND VARIANTS RP VAL-446 AND PRO-553. RC TISSUE=Osteoblast; RA Fisher L.W., McBride O.W., Filpula D., Ibaraki K., Young M.F.; RT "Human drebrin: cDNA sequence, mRNA tissue distribution and chromosomal RT localization."; RL Neurosci. Res. Commun. 14:35-42(1994). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANTS VAL-446 RP AND PRO-553. RC TISSUE=Testis; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15372022; DOI=10.1038/nature02919; RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S., RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.; RT "The DNA sequence and comparative analysis of human chromosome 5."; RL Nature 431:268-274(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), NUCLEOTIDE SEQUENCE RP [LARGE SCALE MRNA] OF 37-521 (ISOFORM 3), AND VARIANTS VAL-446 AND PRO-553. RC TISSUE=Eye, and Muscle; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP PROTEIN SEQUENCE OF 2-10, AND ACETYLATION AT ALA-2. RC TISSUE=Platelet; RX PubMed=12665801; DOI=10.1038/nbt810; RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R., RA Vandekerckhove J.; RT "Exploring proteomes and analyzing protein processing by mass spectrometric RT identification of sorted N-terminal peptides."; RL Nat. Biotechnol. 21:566-569(2003). RN [8] RP PROTEIN SEQUENCE OF 2-10; 43-62; 140-147; 150-165; 272-299 AND 328-390, RP CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, PHOSPHORYLATION AT RP SER-142, AND IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Ovarian carcinoma; RA Bienvenut W.V., Dozynkiewicz M., Norman J.C.; RL Submitted (JUN-2009) to UniProtKB. RN [9] RP PROTEIN SEQUENCE OF 80-94, AND IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Fetal brain cortex; RA Lubec G., Chen W.-Q., Sun Y.; RL Submitted (DEC-2008) to UniProtKB. RN [10] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INVOLVEMENT IN AD. RX PubMed=8838578; DOI=10.1002/jnr.490430111; RA Harigaya Y., Shoji M., Shirao T., Hirai S.; RT "Disappearance of actin-binding protein, drebrin, from hippocampal synapses RT in Alzheimer's disease."; RL J. Neurosci. Res. 43:87-92(1996). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [12] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18220336; DOI=10.1021/pr0705441; RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III; RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient RT phosphoproteomic analysis."; RL J. Proteome Res. 7:1346-1351(2008). RN [13] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Platelet; RX PubMed=18088087; DOI=10.1021/pr0704130; RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J., RA Schuetz C., Walter U., Gambaryan S., Sickmann A.; RT "Phosphoproteome of resting human platelets."; RL J. Proteome Res. 7:526-534(2008). RN [14] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-142; THR-331; THR-335; RP SER-337 AND THR-346, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [15] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-331 AND THR-346, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [17] RP FUNCTION, INTERACTION WITH CXCR4, SUBCELLULAR LOCATION, AND TISSUE RP SPECIFICITY. RX PubMed=20215400; DOI=10.1242/jcs.064238; RA Perez-Martinez M., Gordon-Alonso M., Cabrero J.R., Barrero-Villar M., RA Rey M., Mittelbrunn M., Lamana A., Morlino G., Calabia C., Yamazaki H., RA Shirao T., Vazquez J., Gonzalez-Amaro R., Veiga E., Sanchez-Madrid F.; RT "F-actin-binding protein drebrin regulates CXCR4 recruitment to the immune RT synapse."; RL J. Cell Sci. 123:1160-1170(2010). RN [18] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-141 AND SER-142, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [19] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [20] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-141; SER-142; SER-337 AND RP SER-339, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [21] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-141; SER-142; THR-331; RP SER-337; SER-339 AND THR-346, AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [22] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-416 AND THR-497, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [23] RP INTERACTION WITH ZMYND8. RX PubMed=35916866; DOI=10.1016/j.gim.2022.06.001; RA Dias K.R., Carlston C.M., Blok L.E.R., De Hayr L., Nawaz U., Evans C.A., RA Bayrak-Toydemir P., Htun S., Zhu Y., Ma A., Lynch S.A., Moorwood C., RA Stals K., Ellard S., Bainbridge M.N., Friedman J., Pappas J.G., Rabin R., RA Nowak C.B., Douglas J., Wilson T.E., Guillen Sacoto M.J., Mullegama S.V., RA Palculict T.B., Kirk E.P., Pinner J.R., Edwards M., Montanari F., RA Graziano C., Pippucci T., Dingmann B., Glass I., Mefford H.C., Shimoji T., RA Suzuki T., Yamakawa K., Streff H., Schaaf C.P., Slavotinek A.M., RA Voineagu I., Carey J.C., Buckley M.F., Schenck A., Harvey R.J., RA Roscioli T.; RT "De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental RT disorder with cardiac malformations."; RL Genet. Med. 24:1952-1966(2022). RN [24] {ECO:0007744|PDB:5Y1Z} RP X-RAY CRYSTALLOGRAPHY (2.68 ANGSTROMS) OF 1-135 IN COMPLEX WITH ZMYND8, RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF ARG-10 AND CYS-96. RX PubMed=28966017; DOI=10.1016/j.str.2017.08.014; RA Yao N., Li J., Liu H., Wan J., Liu W., Zhang M.; RT "The Structure of the ZMYND8/Drebrin Complex Suggests a Cytoplasmic RT Sequestering Mechanism of ZMYND8 by Drebrin."; RL Structure 25:1657-1666(2017). RN [25] RP VARIANTS [LARGE SCALE ANALYSIS] LYS-278 AND GLN-640. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). CC -!- FUNCTION: Actin cytoskeleton-organizing protein that plays a role in CC the formation of cell projections (PubMed:20215400). Required for actin CC polymerization at immunological synapses (IS) and for the recruitment CC of the chemokine receptor CXCR4 to IS (PubMed:20215400). Plays a role CC in dendritic spine morphogenesis and organization, including the CC localization of the dopamine receptor DRD1 to the dendritic spines (By CC similarity). Involved in memory-related synaptic plasticity in the CC hippocampus (By similarity). {ECO:0000250|UniProtKB:Q9QXS6, CC ECO:0000269|PubMed:20215400}. CC -!- SUBUNIT: Interacts with RUFY3 (By similarity). Interacts with CXCR4; CC this interaction is enhanced by antigenic stimulation CC (PubMed:20215400). Interacts (via ADF-H domain) with ZMYND8 (via N- CC terminus); the interaction leads to sequestering of ZMYND8 in the CC cytoplasm (PubMed:28966017, PubMed:35916866). CC {ECO:0000250|UniProtKB:Q9QXS6, ECO:0000269|PubMed:20215400, CC ECO:0000269|PubMed:28966017, ECO:0000269|PubMed:35916866}. CC -!- INTERACTION: CC Q16643; P55196: AFDN; NbExp=4; IntAct=EBI-351394, EBI-365875; CC Q16643; P61073: CXCR4; NbExp=5; IntAct=EBI-351394, EBI-489411; CC Q16643; Q16643-1: DBN1; NbExp=2; IntAct=EBI-351394, EBI-8757328; CC Q16643; P62993: GRB2; NbExp=4; IntAct=EBI-351394, EBI-401755; CC Q16643; P28799: GRN; NbExp=5; IntAct=EBI-351394, EBI-747754; CC Q16643; P60484: PTEN; NbExp=5; IntAct=EBI-351394, EBI-696162; CC Q16643; Q9BSI4: TINF2; NbExp=2; IntAct=EBI-351394, EBI-717399; CC Q16643; Q9ULU4: ZMYND8; NbExp=4; IntAct=EBI-351394, EBI-765834; CC Q16643; O35889: Afdn; Xeno; NbExp=3; IntAct=EBI-351394, EBI-6654073; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:20215400, CC ECO:0000269|PubMed:28966017, ECO:0000269|PubMed:8838578}. Cell CC projection, dendrite {ECO:0000269|PubMed:8838578}. Cytoplasm, cell CC cortex {ECO:0000269|PubMed:20215400}. Cell junction CC {ECO:0000269|PubMed:20215400}. Cell projection, growth cone CC {ECO:0000250|UniProtKB:Q9QXS6}. Note=In the absence of antigen, evenly CC distributed throughout subcortical regions of the T-cell membrane and CC cytoplasm (PubMed:20215400). In the presence of antigen, distributes to CC the immunological synapse forming at the T-cell-APC contact area, where CC it localizes at the peripheral and distal supramolecular activation CC clusters (SMAC) (PubMed:20215400). Colocalized with RUFY3 and F-actin CC at the transitional domain of the axonal growth cone (By similarity). CC {ECO:0000250|UniProtKB:Q9QXS6, ECO:0000269|PubMed:20215400}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; Synonyms=Drebrin E, drebrin E2, Embryonic drebrin; CC IsoId=Q16643-1; Sequence=Displayed; CC Name=2; CC IsoId=Q16643-2; Sequence=VSP_028175; CC Name=3; Synonyms=Drebrin A; CC IsoId=Q16643-3; Sequence=VSP_053443; CC -!- TISSUE SPECIFICITY: Expressed in the brain, with expression in the CC molecular layer of the dentate gyrus, stratum pyramidale, and stratum CC radiatum of the hippocampus (at protein level) (PubMed:8838578). Also CC expressed in the terminal varicosities distributed along dendritic CC trees of pyramidal cells in CA4 and CA3 of the hippocampus (at protein CC level) (PubMed:8838578). Expressed in pyramidal cells in CA2, CA1 and CC the subiculum of the hippocampus (at protein level) (PubMed:8838578). CC Expressed in peripheral blood lymphocytes, including T-cells (at CC protein level) (PubMed:20215400). Expressed in the brain CC (PubMed:8216329, Ref.2). Expressed in the heart, placenta, lung, CC skeletal muscle, kidney, pancreas, skin fibroblasts, gingival CC fibroblasts and bone-derived cells (Ref.2). CC {ECO:0000269|PubMed:20215400, ECO:0000269|PubMed:8216329, CC ECO:0000269|PubMed:8838578, ECO:0000269|Ref.2}. CC -!- DISEASE: Alzheimer disease (AD) [MIM:104300]: Alzheimer disease is a CC neurodegenerative disorder characterized by progressive dementia, loss CC of cognitive abilities, and deposition of fibrillar amyloid proteins as CC intraneuronal neurofibrillary tangles, extracellular amyloid plaques CC and vascular amyloid deposits. The major constituents of these plaques CC are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, CC that are produced by the proteolysis of the transmembrane APP protein. CC The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved CC products, such as C31, are also implicated in neuronal death. CC {ECO:0000269|PubMed:8838578}. Note=The protein represented in this CC entry may be involved in disease pathogenesis. In brains of patients CC with AD, decreased expression and absence from dystrophic neurites in CC amyloid plaques. Disappearance of debrin from the hippocampus may CC contribute to the pathogenesis of memory disturbance in AD. CC {ECO:0000269|PubMed:8838578}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; D17530; BAA04480.1; -; mRNA. DR EMBL; U00802; AAA16256.1; -; mRNA. DR EMBL; AK314645; BAG37207.1; -; mRNA. DR EMBL; AL110225; CAB53683.1; -; mRNA. DR EMBL; AC145098; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC000283; AAH00283.1; -; mRNA. DR EMBL; BC007281; AAH07281.1; -; mRNA. DR EMBL; BC007567; AAH07567.1; -; mRNA. DR EMBL; BC114553; -; NOT_ANNOTATED_CDS; mRNA. DR CCDS; CCDS4420.1; -. [Q16643-1] DR CCDS; CCDS4421.1; -. [Q16643-2] DR CCDS; CCDS87354.1; -. [Q16643-3] DR PIR; JN0809; JN0809. DR PIR; T14763; T14763. DR RefSeq; NP_001350470.2; NM_001363541.2. [Q16643-3] DR RefSeq; NP_543157.2; NM_080881.3. [Q16643-2] DR PDB; 5Y1Z; X-ray; 2.68 A; A/B=1-135. DR PDB; 5ZZ9; X-ray; 2.30 A; D/E/F=530-551. DR PDBsum; 5Y1Z; -. DR PDBsum; 5ZZ9; -. DR AlphaFoldDB; Q16643; -. DR SASBDB; Q16643; -. DR SMR; Q16643; -. DR BioGRID; 107995; 435. DR FunCoup; Q16643; 1214. DR IntAct; Q16643; 317. DR MINT; Q16643; -. DR STRING; 9606.ENSP00000377195; -. DR GlyGen; Q16643; 4 sites, 1 O-linked glycan (3 sites). DR iPTMnet; Q16643; -. DR MetOSite; Q16643; -. DR PhosphoSitePlus; Q16643; -. DR SwissPalm; Q16643; -. DR BioMuta; DBN1; -. DR DMDM; 215274247; -. DR OGP; Q16643; -. DR CPTAC; CPTAC-347; -. DR CPTAC; CPTAC-348; -. DR jPOST; Q16643; -. DR MassIVE; Q16643; -. DR PaxDb; 9606-ENSP00000292385; -. DR PeptideAtlas; Q16643; -. DR ProteomicsDB; 2155; -. DR ProteomicsDB; 60996; -. [Q16643-1] DR ProteomicsDB; 60997; -. [Q16643-2] DR Pumba; Q16643; -. DR Antibodypedia; 3641; 373 antibodies from 38 providers. DR DNASU; 1627; -. DR Ensembl; ENST00000292385.9; ENSP00000292385.5; ENSG00000113758.15. [Q16643-2] DR Ensembl; ENST00000309007.9; ENSP00000308532.5; ENSG00000113758.15. [Q16643-1] DR Ensembl; ENST00000393565.6; ENSP00000377195.1; ENSG00000113758.15. [Q16643-3] DR GeneID; 1627; -. DR KEGG; hsa:1627; -. DR MANE-Select; ENST00000393565.6; ENSP00000377195.1; NM_001363541.2; NP_001350470.2. [Q16643-3] DR UCSC; uc003mgx.3; human. [Q16643-1] DR AGR; HGNC:2695; -. DR ClinPGx; PA27163; -. DR CTD; 1627; -. DR DisGeNET; 1627; -. DR GeneCards; DBN1; -. DR HGNC; HGNC:2695; DBN1. DR HPA; ENSG00000113758; Low tissue specificity. DR MIM; 104300; phenotype. DR MIM; 126660; gene. DR OpenTargets; ENSG00000113758; -. DR VEuPathDB; HostDB:ENSG00000113758; -. DR eggNOG; KOG3655; Eukaryota. DR GeneTree; ENSGT00940000159431; -. DR HOGENOM; CLU_013085_3_0_1; -. DR InParanoid; Q16643; -. DR OMA; EEHRWEA; -. DR OrthoDB; 5971719at2759; -. DR PAN-GO; Q16643; 14 GO annotations based on evolutionary models. DR PhylomeDB; Q16643; -. DR PathwayCommons; Q16643; -. DR Reactome; R-HSA-9013405; RHOD GTPase cycle. DR Reactome; R-HSA-9013407; RHOH GTPase cycle. DR Reactome; R-HSA-9013418; RHOBTB2 GTPase cycle. DR Reactome; R-HSA-9013422; RHOBTB1 GTPase cycle. DR SignaLink; Q16643; -. DR SIGNOR; Q16643; -. DR Agora; ENSG00000113758; -. DR BioGRID-ORCS; 1627; 15 hits in 1155 CRISPR screens. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; DBN1; human. DR GeneWiki; DBN1; -. DR GenomeRNAi; 1627; -. DR Pharos; Q16643; Tbio. DR PRO; PR:Q16643; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; Q16643; protein. DR Bgee; ENSG00000113758; Expressed in ganglionic eminence and 199 other cell types or tissues. DR ExpressionAtlas; Q16643; baseline and differential. DR GO; GO:0015629; C:actin cytoskeleton; ISS:UniProtKB. DR GO; GO:0042641; C:actomyosin; NAS:UniProtKB. DR GO; GO:0030863; C:cortical cytoskeleton; TAS:ARUK-UCL. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005856; C:cytoskeleton; IDA:ARUK-UCL. DR GO; GO:0030425; C:dendrite; IDA:UniProtKB. DR GO; GO:0005921; C:gap junction; IEA:Ensembl. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0030426; C:growth cone; ISS:UniProtKB. DR GO; GO:0099524; C:postsynaptic cytosol; IEA:Ensembl. DR GO; GO:0014069; C:postsynaptic density; IEA:Ensembl. DR GO; GO:0045211; C:postsynaptic membrane; IEA:Ensembl. DR GO; GO:0003779; F:actin binding; TAS:ProtInc. DR GO; GO:0045296; F:cadherin binding; HDA:BHF-UCL. DR GO; GO:0005522; F:profilin binding; ISS:UniProtKB. DR GO; GO:0140311; F:protein sequestering activity; IDA:UniProtKB. DR GO; GO:0007015; P:actin filament organization; ISS:UniProtKB. DR GO; GO:0010643; P:cell communication by chemical coupling; IEA:Ensembl. DR GO; GO:0010644; P:cell communication by electrical coupling; IEA:Ensembl. DR GO; GO:0048699; P:generation of neurons; IEA:Ensembl. DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl. DR GO; GO:0032507; P:maintenance of protein location in cell; IEA:Ensembl. DR GO; GO:0061351; P:neural precursor cell proliferation; IEA:Ensembl. DR GO; GO:0061003; P:positive regulation of dendritic spine morphogenesis; ISS:UniProtKB. DR GO; GO:1902685; P:positive regulation of receptor localization to synapse; ISS:UniProtKB. DR GO; GO:0031915; P:positive regulation of synaptic plasticity; ISS:UniProtKB. DR GO; GO:0050773; P:regulation of dendrite development; NAS:UniProtKB. DR GO; GO:0048168; P:regulation of neuronal synaptic plasticity; NAS:UniProtKB. DR CDD; cd11281; ADF_drebrin_like; 1. DR FunFam; 3.40.20.10:FF:000032; Drebrin 1; 1. DR Gene3D; 3.40.20.10; Severin; 1. DR InterPro; IPR002108; ADF-H. DR InterPro; IPR029006; ADF-H/Gelsolin-like_dom_sf. DR PANTHER; PTHR10829; CORTACTIN AND DREBRIN; 1. DR PANTHER; PTHR10829:SF1; DREBRIN; 1. DR Pfam; PF00241; Cofilin_ADF; 1. DR SMART; SM00102; ADF; 1. DR SUPFAM; SSF55753; Actin depolymerizing proteins; 1. DR PROSITE; PS51263; ADF_H; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Actin-binding; Alternative splicing; KW Alzheimer disease; Amyloidosis; Cell junction; Cell projection; Cytoplasm; KW Developmental protein; Differentiation; Direct protein sequencing; KW Neurodegeneration; Neurogenesis; Phosphoprotein; Proteomics identification; KW Reference proteome. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000269|PubMed:12665801, ECO:0000269|Ref.8, FT ECO:0007744|PubMed:19413330" FT CHAIN 2..649 FT /note="Drebrin" FT /id="PRO_0000080008" FT DOMAIN 3..134 FT /note="ADF-H" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00599" FT REGION 208..420 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 477..502 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 538..620 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 208..236 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 288..298 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 334..348 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 363..374 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 582..594 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0000269|PubMed:12665801, ECO:0000269|Ref.8, FT ECO:0007744|PubMed:19413330" FT MOD_RES 141 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 142 FT /note="Phosphoserine" FT /evidence="ECO:0000269|Ref.8, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 331 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163" FT MOD_RES 335 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 337 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 339 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 345 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9QXS6" FT MOD_RES 346 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163" FT MOD_RES 416 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 497 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 601 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9QXS6" FT VAR_SEQ 4..29 FT /note="VSFSGHRLELLAAYEEVIREESAADW -> HPWHGTAALASSQAWRDGRERQ FT ALVSCR (in isoform 2)" FT /evidence="ECO:0000303|PubMed:17974005" FT /id="VSP_028175" FT VAR_SEQ 319 FT /note="G -> GRPYCPFIKASDSGPSSSSSSSSSPPRTPFPYITCHRTPNLSSSLPC FT (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_053443" FT VARIANT 278 FT /note="E -> K (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_035910" FT VARIANT 446 FT /note="I -> V (in dbSNP:rs2544809)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:17974005, ECO:0000269|PubMed:8216329, FT ECO:0000269|Ref.2" FT /id="VAR_047365" FT VARIANT 553 FT /note="S -> P (in dbSNP:rs28538572)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:17974005, ECO:0000269|PubMed:8216329, FT ECO:0000269|Ref.2" FT /id="VAR_047366" FT VARIANT 640 FT /note="E -> Q (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_035911" FT MUTAGEN 10 FT /note="R->D,G: Loss of binding to ZMYND8. Loss of ZMYND8 FT cytoplasmic localization." FT /evidence="ECO:0000269|PubMed:28966017" FT MUTAGEN 96 FT /note="C->Q: Decreased binding to ZMYND8." FT /evidence="ECO:0000269|PubMed:28966017" FT HELIX 10..21 FT /evidence="ECO:0007829|PDB:5Y1Z" FT STRAND 23..26 FT /evidence="ECO:0007829|PDB:5Y1Z" FT STRAND 29..34 FT /evidence="ECO:0007829|PDB:5Y1Z" FT STRAND 40..49 FT /evidence="ECO:0007829|PDB:5Y1Z" FT HELIX 50..54 FT /evidence="ECO:0007829|PDB:5Y1Z" FT HELIX 55..57 FT /evidence="ECO:0007829|PDB:5Y1Z" FT STRAND 62..70 FT /evidence="ECO:0007829|PDB:5Y1Z" FT STRAND 72..74 FT /evidence="ECO:0007829|PDB:5Y1Z" FT STRAND 79..86 FT /evidence="ECO:0007829|PDB:5Y1Z" FT HELIX 92..99 FT /evidence="ECO:0007829|PDB:5Y1Z" FT HELIX 102..108 FT /evidence="ECO:0007829|PDB:5Y1Z" FT STRAND 114..120 FT /evidence="ECO:0007829|PDB:5Y1Z" FT HELIX 121..123 FT /evidence="ECO:0007829|PDB:5Y1Z" FT HELIX 126..132 FT /evidence="ECO:0007829|PDB:5Y1Z" FT HELIX 541..543 FT /evidence="ECO:0007829|PDB:5ZZ9" SQ SEQUENCE 649 AA; 71429 MW; A7DF1AE3776C0BEA CRC64; MAGVSFSGHR LELLAAYEEV IREESAADWA LYTYEDGSDD LKLAASGEGG LQELSGHFEN QKVMYGFCSV KDSQAALPKY VLINWVGEDV PDARKCACAS HVAKVAEFFQ GVDVIVNASS VEDIDAGAIG QRLSNGLARL SSPVLHRLRL REDENAEPVG TTYQKTDAAV EMKRINREQF WEQAKKEEEL RKEEERKKAL DERLRFEQER MEQERQEQEE RERRYREREQ QIEEHRRKQQ TLEAEEAKRR LKEQSIFGDH RDEEEETHMK KSESEVEEAA AIIAQRPDNP REFFKQQERV ASASAGSCDV PSPFNHRPGS HLDSHRRMAP TPIPTRSPSD SSTASTPVAE QIERALDEVT SSQPPPLPPP PPPAQETQEP SPILDSEETR AAAPQAWAGP MEEPPQAQAP PRGPGSPAED LMFMESAEQA VLAAPVEPAT ADATEIHDAA DTIETDTATA DTTVANNVPP AATSLIDLWP GNGEGASTLQ GEPRAPTPPS GTEVTLAEVP LLDEVAPEPL LPAGEGCATL LNFDELPEPP ATFCDPEEVE GESLAAPQTP TLPSALEELE QEQEPEPHLL TNGETTQKEG TQASEGYFSQ SQEEEFAQSE ELCAKAPPPV FYNKPPEIDI TCWDADPVPE EEEGFEGGD // ID E2AK2_HUMAN Reviewed; 551 AA. AC P19525; A8K3P0; D6W584; E9PC80; Q52M43; Q7Z6F6; Q9UIR4; DT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1991, sequence version 2. DT 28-JAN-2026, entry version 260. DE RecName: Full=Interferon-induced, double-stranded RNA-activated protein kinase; DE EC=2.7.11.1; DE AltName: Full=Eukaryotic translation initiation factor 2-alpha kinase 2; DE Short=eIF-2A protein kinase 2; DE AltName: Full=Interferon-inducible RNA-dependent protein kinase; DE AltName: Full=P1/eIF-2A protein kinase; DE AltName: Full=Protein kinase RNA-activated; DE Short=PKR; DE Short=Protein kinase R {ECO:0000303|PubMed:11438532}; DE AltName: Full=Tyrosine-protein kinase EIF2AK2; DE EC=2.7.10.2; DE AltName: Full=p68 kinase; GN Name=EIF2AK2; Synonyms=PKR, PRKR; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 101-118 AND RP 309-325, AND INDUCTION. RX PubMed=1695551; DOI=10.1016/0092-8674(90)90374-n; RA Meurs E., Chong K., Galabru J., Thomas N.S.B., Kerr I.M., Williams B.R.G., RA Hovanessian A.G.; RT "Molecular cloning and characterization of the human double-stranded RNA- RT activated protein kinase induced by interferon."; RL Cell 62:379-390(1990). RN [2] RP SEQUENCE REVISION. RA Meurs E.; RL Submitted (AUG-1990) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=1373553; DOI=10.1016/0042-6822(92)90732-5; RA Thomis D.C., Doohan J.P., Samuel C.E.; RT "Mechanism of interferon action: cDNA structure, expression, and regulation RT of the interferon-induced, RNA-dependent P1/eIF-2 alpha protein kinase from RT human cells."; RL Virology 188:33-46(1992). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1). RX PubMed=8921913; DOI=10.1016/0378-1119(96)00314-9; RA Kuhen K.L., Shen X., Samuel C.E.; RT "Mechanism of interferon action sequence of the human interferon-inducible RT RNA-dependent protein kinase (PKR) deduced from genomic clones."; RL Gene 178:191-193(1996). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC TISSUE=Placenta; RX PubMed=8812437; DOI=10.1006/geno.1996.0446; RA Kuhen K.L., Shen X., Carlisle E.R., Richardson A.L., Weier H.-U.G., RA Tanaka H., Samuel C.E.; RT "Structural organization of the human gene (PKR) encoding an interferon- RT inducible RNA-dependent protein kinase (PKR) and differences from its mouse RT homolog."; RL Genomics 36:197-201(1996). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=9726442; DOI=10.1089/jir.1998.18.609; RA Xu Z., Williams B.R.; RT "Genomic features of human PKR: alternative splicing and a polymorphic CGG RT repeat in the 5'-untranslated region."; RL J. Interferon Cytokine Res. 18:609-616(1998). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RA Li H., Huang F., Shen C., Zhou G., Zheng G., Ke R., Lin L., Yang S.; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain, and Embryo; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NIEHS SNPs program; RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [12] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [13] RP PROTEIN SEQUENCE OF 2-18; 27-40; 70-77; 414-426 AND 430-440, CLEAVAGE OF RP INITIATOR METHIONINE, ACETYLATION AT ALA-2, AND IDENTIFICATION BY MASS RP SPECTROMETRY. RC TISSUE=Prostatic carcinoma; RA Bienvenut W.V., Gao M., Leug H.; RL Submitted (JUN-2009) to UniProtKB. RN [14] RP INTERACTION WITH DNAJC3. RX PubMed=8576172; DOI=10.1074/jbc.271.3.1702; RA Polyak S.J., Tang N., Wambach M., Barber G.N., Katze M.G.; RT "The P58 cellular inhibitor complexes with the interferon-induced, double- RT stranded RNA-dependent protein kinase, PKR, to regulate its RT autophosphorylation and activity."; RL J. Biol. Chem. 271:1702-1707(1996). RN [15] RP INTERACTION WITH HIV-1 TAT. RX PubMed=9079663; DOI=10.1074/jbc.272.13.8388; RA Brand S.R., Kobayashi R., Mathews M.B.; RT "The Tat protein of human immunodeficiency virus type 1 is a substrate and RT inhibitor of the interferon-induced, virally activated protein kinase, RT PKR."; RL J. Biol. Chem. 272:8388-8395(1997). RN [16] RP INTERACTION WITH HCV NON-STRUCTURAL PROTEIN 5A (MICROBIAL INFECTION). RX PubMed=9143277; DOI=10.1006/viro.1997.8493; RA Gale M.J. Jr., Korth M.J., Tang N.M., Tan S.-L., Hopkins D.A., Dever T.E., RA Polyak S.J., Gretch D.R., Katze M.G.; RT "Evidence that hepatitis C virus resistance to interferon is mediated RT through repression of the PKR protein kinase by the nonstructural 5A RT protein."; RL Virology 230:217-227(1997). RN [17] RP INTERACTION WITH HCV NON-STRUCTURAL PROTEIN 5A (MICROBIAL INFECTION). RX PubMed=9710605; DOI=10.1128/mcb.18.9.5208; RA Gale M.J. Jr., Blakely C.M., Kwieciszewski B., Tan S.-L., Dossett M., RA Tang N.M., Korth M.J., Polyak S.J., Gretch D.R., Katze M.G.; RT "Control of PKR protein kinase by hepatitis C virus nonstructural 5A RT protein: molecular mechanisms of kinase regulation."; RL Mol. Cell. Biol. 18:5208-5218(1998). RN [18] RP INTERACTION WITH INFLUENZA A NS1 PROTEIN. RX PubMed=9781815; DOI=10.1089/jir.1998.18.757; RA Tan S.L., Katze M.G.; RT "Biochemical and genetic evidence for complex formation between the RT influenza A virus NS1 protein and the interferon-induced PKR protein RT kinase."; RL J. Interferon Cytokine Res. 18:757-766(1998). RN [19] RP INTERACTION WITH HCV ENVELOPE GLYCOPROTEIN E2 (MICROBIAL INFECTION). RX PubMed=10390359; DOI=10.1126/science.285.5424.107; RA Taylor D.R., Shi S.T., Romano P.R., Barber G.N., Lai M.M.C.; RT "Inhibition of the interferon-inducible protein kinase PKR by HCV E2 RT protein."; RL Science 285:107-110(1999). RN [20] RP FUNCTION, AND INTERACTION WITH IKBKB. RX PubMed=10848580; DOI=10.1128/mcb.20.13.4532-4542.2000; RA Bonnet M.C., Weil R., Dam E., Hovanessian A.G., Meurs E.F.; RT "PKR stimulates NF-kappaB irrespective of its kinase function by RT interacting with the IkappaB kinase complex."; RL Mol. Cell. Biol. 20:4532-4542(2000). RN [21] RP INTERACTION WITH TARBP2. RX PubMed=11438532; DOI=10.1074/jbc.m103584200; RA Daher A., Longuet M., Dorin D., Bois F., Segeral E., Bannwarth S., RA Battisti P.-L., Purcell D.F., Benarous R., Vaquero C., Meurs E.F., RA Gatignol A.; RT "Two dimerization domains in the trans-activation response RNA-binding RT protein (TRBP) individually reverse the protein kinase R inhibition of HIV- RT 1 long terminal repeat expression."; RL J. Biol. Chem. 276:33899-33905(2001). RN [22] RP PHOSPHORYLATION AT SER-83; THR-88; THR-89; THR-90; SER-242; THR-255 AND RP THR-258, MUTAGENESIS OF SER-83; THR-88; THR-89; THR-90; SER-242; THR-255; RP THR-258 AND LYS-296, AND INHIBITION BY HCV E2 ENVELOPE PROTEIN. RX PubMed=11152499; DOI=10.1128/jvi.75.3.1265-1273.2001; RA Taylor D.R., Tian B., Romano P.R., Hinnebusch A.G., Lai M.M.C., RA Mathews M.B.; RT "Hepatitis C virus envelope protein E2 does not inhibit PKR by simple RT competition with autophosphorylation sites in the RNA-binding domain."; RL J. Virol. 75:1265-1273(2001). RN [23] RP MUTAGENESIS OF LYS-60; ALA-67; THR-446 AND THR-451, AND PHOSPHORYLATION AT RP THR-446 AND THR-451. RX PubMed=11337501; DOI=10.1074/jbc.m102108200; RA Zhang F., Romano P.R., Nagamura-Inoue T., Tian B., Dever T.E., RA Mathews M.B., Ozato K., Hinnebusch A.G.; RT "Binding of double-stranded RNA to protein kinase PKR is required for RT dimerization and promotes critical autophosphorylation events in the RT activation loop."; RL J. Biol. Chem. 276:24946-24958(2001). RN [24] RP INTERACTION WITH HHV-8 PROTEIN VIRF2 (MICROBIAL INFECTION). RX PubMed=11160738; DOI=10.1128/jvi.75.5.2345-2352.2001; RA Burysek L., Pitha P.M.; RT "Latently expressed human herpesvirus 8-encoded interferon regulatory RT factor 2 inhibits double-stranded RNA-activated protein kinase."; RL J. Virol. 75:2345-2352(2001). RN [25] RP FUNCTION, AND INTERACTION WITH HHV-1 US11 (MICROBIAL INFECTION). RX PubMed=11836380; DOI=10.1128/jvi.76.5.2029-2035.2002; RA Cassady K.A., Gross M.; RT "The herpes simplex virus type 1 U(S)11 protein interacts with protein RT kinase R in infected cells and requires a 30-amino-acid sequence adjacent RT to a kinase substrate domain."; RL J. Virol. 76:2029-2035(2002). RN [26] RP INTERACTION WITH NPM1, AND ACTIVITY REGULATION. RX PubMed=12882984; DOI=10.1074/jbc.m301392200; RA Pang Q., Christianson T.A., Koretsky T., Carlson H., David L., Keeble W., RA Faulkner G.R., Speckhart A., Bagby G.C.; RT "Nucleophosmin interacts with and inhibits the catalytic function of RT eukaryotic initiation factor 2 kinase PKR."; RL J. Biol. Chem. 278:41709-41717(2003). RN [27] RP FUNCTION, AND INTERACTION WITH MAP2K6. RX PubMed=15229216; DOI=10.1074/jbc.m406554200; RA Silva A.M., Whitmore M., Xu Z., Jiang Z., Li X., Williams B.R.; RT "Protein kinase R (PKR) interacts with and activates mitogen-activated RT protein kinase kinase 6 (MKK6) in response to double-stranded RNA RT stimulation."; RL J. Biol. Chem. 279:37670-37676(2004). RN [28] RP IDENTIFICATION IN A COMPLEX WITH FANCA; FANCC; FANCG AND HSP70. RX PubMed=15299030; DOI=10.1074/jbc.m403884200; RA Zhang X., Li J., Sejas D.P., Rathbun K.R., Bagby G.C., Pang Q.; RT "The Fanconi anemia proteins functionally interact with the protein kinase RT regulated by RNA (PKR)."; RL J. Biol. Chem. 279:43910-43919(2004). RN [29] RP FUNCTION, INTERACTION WITH TRAF2; TRAF5 AND TRAF6, AND SUBCELLULAR RP LOCATION. RX PubMed=15121867; DOI=10.1128/mcb.24.10.4502-4512.2004; RA Gil J., Garcia M.A., Gomez-Puertas P., Guerra S., Rullas J., Nakano H., RA Alcami J., Esteban M.; RT "TRAF family proteins link PKR with NF-kappa B activation."; RL Mol. Cell. Biol. 24:4502-4512(2004). RN [30] RP INHIBITION BY VACCINIA VIRUS PROTEIN E3 (MICROBIAL INFECTION). RX PubMed=15207627; DOI=10.1016/j.virol.2004.03.012; RA Langland J.O., Jacobs B.L.; RT "Inhibition of PKR by vaccinia virus: role of the N- and C-terminal domains RT of E3L."; RL Virology 324:419-429(2004). RN [31] RP REVIEW. RX PubMed=17158706; DOI=10.1128/mmbr.00027-06; RA Garcia M.A., Gil J., Ventoso I., Guerra S., Domingo E., Rivas C., RA Esteban M.; RT "Impact of protein kinase PKR in cell biology: from antiviral to RT antiproliferative action."; RL Microbiol. Mol. Biol. Rev. 70:1032-1060(2006). RN [32] RP INTERACTION WITH HCMV TRS1 (MICROBIAL INFECTION). RX PubMed=16987971; DOI=10.1128/jvi.00957-06; RA Hakki M., Marshall E.E., De Niro K.L., Geballe A.P.; RT "Binding and nuclear relocalization of protein kinase R by human RT cytomegalovirus TRS1."; RL J. Virol. 80:11817-11826(2006). RN [33] RP PHOSPHORYLATION AT TYR-101; TYR-162 AND TYR-293. RX PubMed=16373505; DOI=10.1073/pnas.0508207103; RA Su Q., Wang S., Baltzis D., Qu L.K., Wong A.H., Koromilas A.E.; RT "Tyrosine phosphorylation acts as a molecular switch to full-scale RT activation of the eIF2alpha RNA-dependent protein kinase."; RL Proc. Natl. Acad. Sci. U.S.A. 103:63-68(2006). RN [34] RP INTERACTION WITH HCV NON-STRUCTURAL PROTEIN 5A (MICROBIAL INFECTION). RX PubMed=16951545; DOI=10.1016/s1016-8478(23)17385-7; RA Liang Y., Kang C.B., Yoon H.S.; RT "Molecular and structural characterization of the domain 2 of hepatitis C RT virus non-structural protein 5A."; RL Mol. Cells 22:13-20(2006). RN [35] RP INTERACTION WITH HCV NON-STRUCTURAL PROTEIN 5A (MICROBIAL INFECTION). RX PubMed=17451199; DOI=10.3748/wjg.v13.i8.1195; RA Veillon P., Payan C., Le Guillou-Guillemette H., Gaudy C., Lunel F.; RT "Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b RT during interferon or combined interferon-ribavirin therapy."; RL World J. Gastroenterol. 13:1195-1203(2007). RN [36] RP INTERACTION WITH HCV MATURE CORE PROTEIN (MICROBIAL INFECTION). RX PubMed=17267064; DOI=10.1016/j.virusres.2006.12.010; RA Yan X.B., Battaglia S., Boucreux D., Chen Z., Brechot C., Pavio N.; RT "Mapping of the interacting domains of hepatitis C virus core protein and RT the double-stranded RNA-activated protein kinase PKR."; RL Virus Res. 125:79-87(2007). RN [37] RP INTERACTION WITH ADAR. RX PubMed=17079286; DOI=10.1128/jvi.01527-06; RA Nie Y., Hammond G.L., Yang J.H.; RT "Double-stranded RNA deaminase ADAR1 increases host susceptibility to virus RT infection."; RL J. Virol. 81:917-923(2007). RN [38] RP REVIEW ON ACTIVITY REGULATION. RX PubMed=17196820; DOI=10.1016/j.tibs.2006.12.003; RA Cole J.L.; RT "Activation of PKR: an open and shut case?"; RL Trends Biochem. Sci. 32:57-62(2007). RN [39] RP FUNCTION, INTERACTION WITH NCK1, AND ACTIVITY REGULATION. RX PubMed=18835251; DOI=10.1016/j.bbrc.2008.09.112; RA Cardin E., Larose L.; RT "Nck-1 interacts with PKR and modulates its activation by dsRNA."; RL Biochem. Biophys. Res. Commun. 377:231-235(2008). RN [40] RP INTERACTION WITH DUS2L, AND ACTIVITY REGULATION. RX PubMed=18096616; DOI=10.1093/nar/gkm1129; RA Mittelstadt M., Frump A., Khuu T., Fowlkes V., Handy I., Patel C.V., RA Patel R.C.; RT "Interaction of human tRNA-dihydrouridine synthase-2 with interferon- RT induced protein kinase PKR."; RL Nucleic Acids Res. 36:998-1008(2008). RN [41] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83 AND SER-456, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [42] RP MUTAGENESIS OF ASP-486, AND INTERACTION WITH VACCINIA VIRUS PROTEIN K3 RP (MICROBIAL INFECTION). RX PubMed=18971339; DOI=10.1073/pnas.0805524105; RA Seo E.J., Liu F., Kawagishi-Kobayashi M., Ung T.L., Cao C., Dar A.C., RA Sicheri F., Dever T.E.; RT "Protein kinase PKR mutants resistant to the poxvirus pseudosubstrate K3L RT protein."; RL Proc. Natl. Acad. Sci. U.S.A. 105:16894-16899(2008). RN [43] RP FUNCTION. RX PubMed=19507191; DOI=10.1002/jcp.21848; RA Blalock W.L., Grimaldi C., Fala F., Follo M., Horn S., Basecke J., RA Martinelli G., Cocco L., Martelli A.M.; RT "PKR activity is required for acute leukemic cell maintenance and growth: a RT role for PKR-mediated phosphatase activity to regulate GSK-3 RT phosphorylation."; RL J. Cell. Physiol. 221:232-241(2009). RN [44] RP FUNCTION, AND INTERACTION WITH DHX9. RX PubMed=19229320; DOI=10.1371/journal.ppat.1000311; RA Sadler A.J., Latchoumanin O., Hawkes D., Mak J., Williams B.R.; RT "An antiviral response directed by PKR phosphorylation of the RNA helicase RT A."; RL PLoS Pathog. 5:E1000311-E1000311(2009). RN [45] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [46] RP FUNCTION IN HCV RESTRICTION. RX PubMed=19189853; DOI=10.1016/j.virusres.2009.01.007; RA Kang J.I., Kwon S.N., Park S.H., Kim Y.K., Choi S.Y., Kim J.P., Ahn B.Y.; RT "PKR protein kinase is activated by hepatitis C virus and inhibits viral RT replication through translational control."; RL Virus Res. 142:51-56(2009). RN [47] RP FUNCTION. RX PubMed=20171114; DOI=10.1016/j.cyto.2010.01.008; RA Lin S.S., Lee D.C., Law A.H., Fang J.W., Chua D.T., Lau A.S.; RT "A role for protein kinase PKR in the mediation of Epstein-Barr virus RT latent membrane protein-1-induced IL-6 and IL-10 expression."; RL Cytokine 50:210-219(2010). RN [48] RP FUNCTION AS CDK1 KINASE UPON DNA DAMAGE, AND FUNCTION AS TYROSINE-PROTEIN RP KINASE. RX PubMed=20395957; DOI=10.1038/embor.2010.45; RA Yoon C.-H., Miah M.A., Kim K.P., Bae Y.-S.; RT "New Cdc2 Tyr 4 phosphorylation by dsRNA-activated protein kinase triggers RT Cdc2 polyubiquitination and G2 arrest under genotoxic stresses."; RL EMBO Rep. 11:393-399(2010). RN [49] RP FUNCTION. RX PubMed=21123651; DOI=10.1101/gad.1965010; RA Harashima A., Guettouche T., Barber G.N.; RT "Phosphorylation of the NFAR proteins by the dsRNA-dependent protein kinase RT PKR constitutes a novel mechanism of translational regulation and cellular RT defense."; RL Genes Dev. 24:2640-2653(2010). RN [50] RP INTERACTION WITH HRSV NUCLEOPROTEIN (MICROBIAL INFECTION). RX PubMed=20519500; DOI=10.1074/jbc.m109.077321; RA Groskreutz D.J., Babor E.C., Monick M.M., Varga S.M., Hunninghake G.W.; RT "Respiratory syncytial virus limits alpha subunit of eukaryotic translation RT initiation factor 2 (eIF2alpha) phosphorylation to maintain translation and RT viral replication."; RL J. Biol. Chem. 285:24023-24031(2010). RN [51] RP FUNCTION IN HCV RESTRICTION. RX PubMed=19840259; DOI=10.1111/j.1478-3231.2009.02144.x; RA Chang J.H., Kato N., Muroyama R., Taniguchi H., Guleng B., Dharel N., RA Shao R.X., Tateishi K., Jazag A., Kawabe T., Omata M.; RT "Double-stranded RNA-activated protein kinase inhibits hepatitis C virus RT replication but may be not essential in interferon treatment."; RL Liver Int. 30:311-318(2010). RN [52] RP FUNCTION, AND PHOSPHORYLATION AT THR-451. RX PubMed=20685959; DOI=10.1091/mbc.e10-06-0481; RA Yang X., Nath A., Opperman M.J., Chan C.; RT "The double-stranded RNA-dependent protein kinase differentially regulates RT insulin receptor substrates 1 and 2 in HepG2 cells."; RL Mol. Biol. Cell 21:3449-3458(2010). RN [53] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [54] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [55] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND PHOSPHORYLATION. RX PubMed=21029237; DOI=10.1111/j.1750-3639.2010.00437.x; RA Bose A., Mouton-Liger F., Paquet C., Mazot P., Vigny M., Gray F., Hugon J.; RT "Modulation of tau phosphorylation by the kinase PKR: implications in RT Alzheimer's disease."; RL Brain Pathol. 21:189-200(2011). RN [56] RP REVIEW. RX PubMed=21924887; DOI=10.1016/j.coi.2011.08.009; RA Pfaller C.K., Li Z., George C.X., Samuel C.E.; RT "Protein kinase PKR and RNA adenosine deaminase ADAR1: new roles for old RT players as modulators of the interferon response."; RL Curr. Opin. Immunol. 23:573-582(2011). RN [57] RP REVIEW. RX PubMed=21166592; DOI=10.1089/jir.2010.0099; RA Pindel A., Sadler A.; RT "The role of protein kinase R in the interferon response."; RL J. Interferon Cytokine Res. 31:59-70(2011). RN [58] RP FUNCTION, SUBCELLULAR LOCATION, IDENTIFICATION BY MASS SPECTROMETRY, AND RP PHOSPHORYLATION. RX PubMed=21072047; DOI=10.1038/leu.2010.264; RA Blalock W.L., Bavelloni A., Piazzi M., Tagliavini F., Faenza I., RA Martelli A.M., Follo M.Y., Cocco L.; RT "Multiple forms of PKR present in the nuclei of acute leukemia cells RT represent an active kinase that is responsive to stress."; RL Leukemia 25:236-245(2011). RN [59] RP FUNCTION IN HBV RESTRICTION. RX PubMed=21710204; DOI=10.1007/s10059-011-1059-6; RA Park I.H., Baek K.W., Cho E.Y., Ahn B.Y.; RT "PKR-dependent mechanisms of interferon-? for inhibiting hepatitis B virus RT replication."; RL Mol. Cells 32:167-172(2011). RN [60] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=22214662; DOI=10.4161/cc.11.2.18999; RA Bennett R.L., Pan Y., Christian J., Hui T., May W.S. Jr.; RT "The RAX/PACT-PKR stress response pathway promotes p53 sumoylation and RT activation, leading to G(1) arrest."; RL Cell Cycle 11:407-417(2012). RN [61] RP REVIEW. RX PubMed=22633454; DOI=10.1016/j.immuni.2012.05.010; RA Lacy-Hulbert A., Stuart L.M.; RT "Penetration resistance: PKR's other talent."; RL Immunity 36:695-696(2012). RN [62] RP FUNCTION. RX PubMed=22948139; DOI=10.1074/jbc.m112.390039; RA McAllister C.S., Taghavi N., Samuel C.E.; RT "Protein kinase PKR amplification of interferon beta induction occurs RT through initiation factor eIF-2alpha-mediated translational control."; RL J. Biol. Chem. 287:36384-36392(2012). RN [63] RP FUNCTION, AND INTERACTION WITH STAT3. RX PubMed=23084476; DOI=10.1016/j.molcel.2012.09.013; RA Shen S., Niso-Santano M., Adjemian S., Takehara T., Malik S.A., Minoux H., RA Souquere S., Marino G., Lachkar S., Senovilla L., Galluzzi L., Kepp O., RA Pierron G., Maiuri M.C., Hikita H., Kroemer R., Kroemer G.; RT "Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity."; RL Mol. Cell 48:667-680(2012). RN [64] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=22223895; DOI=10.1074/mcp.m111.015131; RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T., RA Giglione C.; RT "Comparative large-scale characterisation of plant vs. mammal proteins RT reveals similar and idiosyncratic N-alpha acetylation features."; RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012). RN [65] RP FUNCTION, INTERACTION WITH NLRP1; NLRP3; NLRC4 AND AIM2, AND RP AUTOPHOSPHORYLATION. RX PubMed=22801494; DOI=10.1038/nature11290; RA Lu B., Nakamura T., Inouye K., Li J., Tang Y., Lundbaeck P., RA Valdes-Ferrer S.I., Olofsson P.S., Kalb T., Roth J., Zou Y., RA Erlandsson-Harris H., Yang H., Ting J.P., Wang H., Andersson U., RA Antoine D.J., Chavan S.S., Hotamisligil G.S., Tracey K.J.; RT "Novel role of PKR in inflammasome activation and HMGB1 release."; RL Nature 488:670-674(2012). RN [66] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [67] RP REVIEW. RX PubMed=23092889; DOI=10.1126/scisignal.2003511; RA Kang R., Tang D.; RT "PKR-dependent inflammatory signals."; RL Sci. Signal. 5:PE47-PE47(2012). RN [68] RP FUNCTION. RX PubMed=22381929; DOI=10.1016/j.virol.2012.01.029; RA Taghavi N., Samuel C.E.; RT "Protein kinase PKR catalytic activity is required for the PKR-dependent RT activation of mitogen-activated protein kinases and amplification of RT interferon beta induction following virus infection."; RL Virology 427:208-216(2012). RN [69] RP REVIEW. RX PubMed=23202496; DOI=10.3390/v4112598; RA Dabo S., Meurs E.F.; RT "dsRNA-dependent protein kinase PKR and its role in stress, signaling and RT HCV infection."; RL Viruses 4:2598-2635(2012). RN [70] RP TISSUE SPECIFICITY. RX PubMed=23403623; DOI=10.1182/blood-2012-09-456400; RA Liu X., Bennett R.L., Cheng X., Byrne M., Reinhard M.K., May W.S. Jr.; RT "PKR regulates proliferation, differentiation and survival of murine RT hematopoietic stem/progenitor cells."; RL Blood 121:3364-3374(2013). RN [71] RP REVIEW. RX PubMed=23354059; DOI=10.1007/s00018-012-1252-6; RA Donnelly N., Gorman A.M., Gupta S., Samali A.; RT "The eIF2alpha kinases: their structures and functions."; RL Cell. Mol. Life Sci. 70:3493-3511(2013). RN [72] RP FUNCTION, ISGYLATION AT LYS-69 AND LYS-159, AND ACTIVITY REGULATION. RX PubMed=23229543; DOI=10.1074/jbc.m112.401851; RA Okumura F., Okumura A.J., Uematsu K., Hatakeyama S., Zhang D.E., Kamura T.; RT "Activation of double-stranded RNA-activated protein kinase (PKR) by RT interferon-stimulated gene 15 (ISG15) modification down-regulates protein RT translation."; RL J. Biol. Chem. 288:2839-2847(2013). RN [73] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-542, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [74] RP INTERACTION WITH TOSCANA VIRUS PROTEIN NSS (MICROBIAL INFECTION), AND RP ACTIVITY REGULATION. RX PubMed=23325696; DOI=10.1128/jvi.02506-12; RA Kalveram B., Ikegami T.; RT "Toscana virus NSs protein promotes degradation of double-stranded RNA- RT dependent protein kinase."; RL J. Virol. 87:3710-3718(2013). RN [75] RP FUNCTION IN MV RESTRICTION. RX PubMed=23115276; DOI=10.1128/jvi.02270-12; RA Okonski K.M., Samuel C.E.; RT "Stress granule formation induced by measles virus is protein kinase PKR RT dependent and impaired by RNA adenosine deaminase ADAR1."; RL J. Virol. 87:756-766(2013). RN [76] RP FUNCTION. RX PubMed=23372823; DOI=10.1371/journal.pone.0055108; RA Li Y., Xie J., Wu S., Xia J., Zhang P., Liu C., Zhang P., Huang X.; RT "Protein kinase regulated by dsRNA downregulates the interferon production RT in dengue virus- and dsrna-stimulated human lung epithelial cells."; RL PLoS ONE 8:E55108-E55108(2013). RN [77] RP FUNCTION IN HCV RESTRICTION. RX PubMed=23399035; DOI=10.1016/j.virol.2013.01.015; RA Zhang L., Alter H.J., Wang H., Jia S., Wang E., Marincola F.M., Shih J.W., RA Wang R.Y.; RT "The modulation of hepatitis C virus 1a replication by PKR is dependent on RT NF-kB mediated interferon beta response in Huh7.5.1 cells."; RL Virology 438:28-36(2013). RN [78] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [79] RP INTERACTION WITH VACCINIA VIRUS PROTEIN E3 (MICROBIAL INFECTION). RX PubMed=25740987; DOI=10.1128/jvi.03288-14; RA Dueck K.J., Hu Y.S., Chen P., Deschambault Y., Lee J., Varga J., Cao J.; RT "Mutational analysis of vaccinia virus E3 protein: the biological functions RT do not correlate with its biochemical capacity to bind double-stranded RT RNA."; RL J. Virol. 89:5382-5394(2015). RN [80] RP INTERACTION WITH MBIP AND MOCS2B, SUBCELLULAR LOCATION, AND RP PHOSPHORYLATION. RX PubMed=26705305; DOI=10.1093/jmcb/mjv070; RA Suganuma T., Swanson S.K., Florens L., Washburn M.P., Workman J.L.; RT "Moco biosynthesis and the ATAC acetyltransferase engage translation RT initiation by inhibiting latent PKR activity."; RL J. Mol. Cell Biol. 8:44-50(2016). RN [81] RP MUTAGENESIS OF PHE-489; THR-496; ILE-502; LYS-510 AND GLN-516, RP CHARACTERIZATION OF VARIANT VAL-506, AND INTERACTION WITH HCMV TRS1 RP (MICROBIAL INFECTION). RX PubMed=27780231; DOI=10.1371/journal.ppat.1005966; RA Carpentier K.S., Esparo N.M., Child S.J., Geballe A.P.; RT "A Single Amino Acid Dictates Protein Kinase R Susceptibility to Unrelated RT Viral Antagonists."; RL PLoS Pathog. 12:e1005966-e1005966(2016). RN [82] RP INTERACTION WITH HUMAN HERPES VIRUS 8 PROTEIN KTA/ORF57 (MICROBIAL RP INFECTION). RX PubMed=29084250; DOI=10.1371/journal.ppat.1006677; RA Sharma N.R., Majerciak V., Kruhlak M.J., Zheng Z.M.; RT "KSHV inhibits stress granule formation by viral ORF57 blocking PKR RT activation."; RL PLoS Pathog. 13:e1006677-e1006677(2017). RN [83] {ECO:0007744|PDB:1QU6} RP STRUCTURE BY NMR OF 1-170, AND DOMAIN. RX PubMed=9736623; DOI=10.1093/emboj/17.18.5458; RA Nanduri S., Carpick B.W., Yang Y., Williams B.R.G., Qin J.; RT "Structure of the double-stranded RNA-binding domain of the protein kinase RT PKR reveals the molecular basis of its dsRNA-mediated activation."; RL EMBO J. 17:5458-5465(1998). RN [84] {ECO:0007744|PDB:2A19, ECO:0007744|PDB:2A1A} RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 258-550 IN COMPLEX WITH RP EIF2S1/EIF-2ALPHA, PHOSPHORYLATION AT THR-446, DOMAIN, SUBUNIT, COFACTOR, RP AND INTERACTION WITH EIF2S1/EIF-2ALPHA. RX PubMed=16179258; DOI=10.1016/j.cell.2005.06.044; RA Dar A.C., Dever T.E., Sicheri F.; RT "Higher-order substrate recognition of eIF2alpha by the RNA-dependent RT protein kinase PKR."; RL Cell 122:887-900(2005). RN [85] {ECO:0007744|PDB:6D3K, ECO:0007744|PDB:6D3L} RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 229-551, AND SUBUNIT. RX PubMed=31246429; DOI=10.1021/acs.biochem.9b00161; RA Mayo C.B., Erlandsen H., Mouser D.J., Feinstein A.G., Robinson V.L., RA May E.R., Cole J.L.; RT "Structural Basis of Protein Kinase R Autophosphorylation."; RL Biochemistry 58:2967-2977(2019). RN [86] RP INVOLVEMENT IN LEUDEN, FUNCTION, VARIANTS LEUDEN LEU-11; SER-32; PHE-97; RP SER-109; VAL-109; PHE-133; SER-325 AND CYS-461, CHARACTERIZATION OF RP VARIANTS LEUDEN LEU-11; PHE-133 AND CYS-461, AND VARIANT GLN-114. RX PubMed=32197074; DOI=10.1016/j.ajhg.2020.02.016; RG Undiagnosed Diseases Network; RA Mao D., Reuter C.M., Ruzhnikov M.R.Z., Beck A.E., Farrow E.G., Emrick L.T., RA Rosenfeld J.A., Mackenzie K.M., Robak L., Wheeler M.T., Burrage L.C., RA Jain M., Liu P., Calame D., Kuery S., Sillesen M., Schmitz-Abe K., RA Tonduti D., Spaccini L., Iascone M., Genetti C.A., Koenig M.K., Graf M., RA Tran A., Alejandro M., Lee B.H., Thiffault I., Agrawal P.B., RA Bernstein J.A., Bellen H.J., Chao H.T.; RT "De novo EIF2AK1 and EIF2AK2 variants are associated with developmental RT delay, leukoencephalopathy, and neurologic decompensation."; RL Am. J. Hum. Genet. 106:570-583(2020). RN [87] RP VARIANTS [LARGE SCALE ANALYSIS] GLU-428; VAL-439 AND VAL-506. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [88] RP VARIANTS DYT33 THR-32; ARG-130 AND ALA-138, CHARACTERIZATION OF VARIANTS RP DYT33 THR-32 AND ARG-130, AND INVOLVEMENT IN DYT33. RX PubMed=33236446; DOI=10.1002/ana.25973; RA Kuipers D.J.S., Mandemakers W., Lu C.S., Olgiati S., Breedveld G.J., RA Fevga C., Tadic V., Carecchio M., Osterman B., Sagi-Dain L., Wu-Chou Y.H., RA Chen C.C., Chang H.C., Wu S.L., Yeh T.H., Weng Y.H., Elia A.E., RA Panteghini C., Marotta N., Pauly M.G., Kuehn A.A., Volkmann J., Lace B., RA Meijer I.A., Kandaswamy K., Quadri M., Garavaglia B., Lohmann K., Bauer P., RA Mencacci N.E., Lubbe S.J., Klein C., Bertoli-Avella A.M., Bonifati V.; RT "EIF2AK2 Missense Variants Associated with Early Onset Generalized RT Dystonia."; RL Ann. Neurol. 89:485-497(2021). RN [89] RP VARIANT DYT33 ARG-130, AND INVOLVEMENT IN DYT33. RX PubMed=33866603; DOI=10.1002/ana.26081; RA Musacchio T., Zech M., Reich M.M., Winkelmann J., Volkmann J.; RT "A Recurrent EIF2AK2 Missense Variant Causes Autosomal-Dominant Isolated RT Dystonia."; RL Ann. Neurol. 89:1257-1258(2021). RN [90] RP VARIANT DYT33 ARG-130. RX PubMed=35146068; DOI=10.1002/mdc3.13371; RA Magrinelli F., Moualek D., Tazir M., Pacha L.A., Verghese A., Bhatia K.P., RA Maroofian R., Houlden H.; RT "Heterozygous EIF2AK2 Variant Causes Adolescence-Onset Generalized Dystonia RT Partially Responsive to DBS."; RL Mov. Disord. Clin. Pract. 9:268-271(2022). CC -!- FUNCTION: IFN-induced dsRNA-dependent serine/threonine-protein kinase CC that phosphorylates the alpha subunit of eukaryotic translation CC initiation factor 2 (EIF2S1/eIF-2-alpha) and plays a key role in the CC innate immune response to viral infection (PubMed:18835251, CC PubMed:19189853, PubMed:19507191, PubMed:21072047, PubMed:21123651, CC PubMed:22381929, PubMed:22948139, PubMed:23229543). Inhibits viral CC replication via the integrated stress response (ISR): EIF2S1/eIF-2- CC alpha phosphorylation in response to viral infection converts CC EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, resulting CC to a shutdown of cellular and viral protein synthesis, while CC concomitantly initiating the preferential translation of ISR-specific CC mRNAs, such as the transcriptional activator ATF4 (PubMed:19189853, CC PubMed:21123651, PubMed:22948139, PubMed:23229543). Exerts its CC antiviral activity on a wide range of DNA and RNA viruses including CC hepatitis C virus (HCV), hepatitis B virus (HBV), measles virus (MV) CC and herpes simplex virus 1 (HHV-1) (PubMed:11836380, PubMed:19189853, CC PubMed:19840259, PubMed:20171114, PubMed:21710204, PubMed:23115276, CC PubMed:23399035). Also involved in the regulation of signal CC transduction, apoptosis, cell proliferation and differentiation: CC phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, CC ILF3, IRS1 and the HHV-1 viral protein US11 (PubMed:11836380, CC PubMed:19229320, PubMed:22214662). In addition to serine/threonine- CC protein kinase activity, also has tyrosine-protein kinase activity and CC phosphorylates CDK1 at 'Tyr-4' upon DNA damage, facilitating its CC ubiquitination and proteasomal degradation (PubMed:20395957). Either as CC an adapter protein and/or via its kinase activity, can regulate various CC signaling pathways (p38 MAP kinase, NF-kappa-B and insulin signaling CC pathways) and transcription factors (JUN, STAT1, STAT3, IRF1, ATF3) CC involved in the expression of genes encoding pro-inflammatory cytokines CC and IFNs (PubMed:22948139, PubMed:23084476, PubMed:23372823). Activates CC the NF-kappa-B pathway via interaction with IKBKB and TRAF family of CC proteins and activates the p38 MAP kinase pathway via interaction with CC MAP2K6 (PubMed:10848580, PubMed:15121867, PubMed:15229216). Can act as CC both a positive and negative regulator of the insulin signaling pathway CC (ISP) (PubMed:20685959). Negatively regulates ISP by inducing the CC inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) at CC 'Ser-312' and positively regulates ISP via phosphorylation of PPP2R5A CC which activates FOXO1, which in turn up-regulates the expression of CC insulin receptor substrate 2 (IRS2) (PubMed:20685959). Can regulate CC NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 CC and NLRC4 inflammasomes (PubMed:22801494). Plays a role in the CC regulation of the cytoskeleton by binding to gelsolin (GSN), CC sequestering the protein in an inactive conformation away from actin CC (By similarity). {ECO:0000250|UniProtKB:Q03963, CC ECO:0000269|PubMed:10848580, ECO:0000269|PubMed:11836380, CC ECO:0000269|PubMed:15121867, ECO:0000269|PubMed:15229216, CC ECO:0000269|PubMed:18835251, ECO:0000269|PubMed:19189853, CC ECO:0000269|PubMed:19229320, ECO:0000269|PubMed:19507191, CC ECO:0000269|PubMed:19840259, ECO:0000269|PubMed:20171114, CC ECO:0000269|PubMed:20395957, ECO:0000269|PubMed:20685959, CC ECO:0000269|PubMed:21072047, ECO:0000269|PubMed:21123651, CC ECO:0000269|PubMed:21710204, ECO:0000269|PubMed:22214662, CC ECO:0000269|PubMed:22381929, ECO:0000269|PubMed:22801494, CC ECO:0000269|PubMed:22948139, ECO:0000269|PubMed:23084476, CC ECO:0000269|PubMed:23115276, ECO:0000269|PubMed:23229543, CC ECO:0000269|PubMed:23372823, ECO:0000269|PubMed:23399035, CC ECO:0000269|PubMed:32197074}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + CC H(+); Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + CC ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA- CC COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + CC ADP + H(+); Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- CC COMP:20101, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, CC ChEBI:CHEBI:61978, ChEBI:CHEBI:456216; EC=2.7.10.2; CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10027}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:16179258, ECO:0000303|PubMed:31246429}; CC -!- ACTIVITY REGULATION: Initially produced in an inactive form and is CC activated by binding to viral dsRNA, which causes dimerization and CC autophosphorylation in the activation loop and stimulation of function. CC ISGylation can activate it in the absence of viral infection. Can also CC be activated by heparin, pro-inflammatory stimuli, growth factors, CC cytokines, oxidative stress and the cellular protein PRKRA. Activity is CC markedly stimulated by manganese ions. Activation is blocked by the CC viral components HIV-1 Tat protein and large amounts of HIV-1 trans- CC activation response (TAR) RNA element as well as by the cellular CC proteins TARBP2, DUS2L, NPM1, NCK1 and ADAR. Down-regulated by Toscana CC virus (TOS) and Rift valley fever virus (RVFV) NSS which promote its CC proteasomal degradation. Inhibited by vaccinia virus protein E3, CC probably via dsRNA sequestering. {ECO:0000269|PubMed:12882984, CC ECO:0000269|PubMed:18096616, ECO:0000269|PubMed:18835251, CC ECO:0000269|PubMed:23229543, ECO:0000269|PubMed:23325696}. CC -!- SUBUNIT: Homodimer (PubMed:16179258, PubMed:31246429). Interacts with CC STRBP (By similarity). Interacts with DNAJC3. Forms a complex with CC FANCA, FANCC, FANCG and HSP70. Interacts with ADAR/ADAR1. Interacts CC with IRS1 (By similarity). The inactive form interacts with NCK1 and CC GSN. Interacts (via the kinase catalytic domain) with STAT3 (via SH2 CC domain), TRAF2 (C-terminus), TRAF5 (C-terminus) and TRAF6 (C-terminus). CC Interacts with MAP2K6, IKBKB/IKKB, NPM1, TARBP2, NLRP1, NLRP3, NLRC4 CC and AIM2. Interacts (via DRBM 1 domain) with DUS2L (via DRBM domain). CC Interacts with DHX9 (via N-terminus) and this interaction is dependent CC upon activation of the kinase. Interacts with EIF2S1/EIF-2ALPHA; this CC interaction induces a conformational change in EIF2S1 and its CC phosphorylation by EIF2AK2 (PubMed:16179258). Interacts with MBIP; the CC interaction is direct and leads to inhibition of EIF2AK2 self- CC activating autophosphorylation (PubMed:26705305). Interacts with the CC molybdopterin synthase complex subunit MOCS2B; the interaction is CC direct and enhances the interaction between EIF2AK2 and MBIP CC (PubMed:26705305). {ECO:0000250|UniProtKB:Q03963, CC ECO:0000269|PubMed:10390359, ECO:0000269|PubMed:10848580, CC ECO:0000269|PubMed:11438532, ECO:0000269|PubMed:12882984, CC ECO:0000269|PubMed:15121867, ECO:0000269|PubMed:15229216, CC ECO:0000269|PubMed:15299030, ECO:0000269|PubMed:16179258, CC ECO:0000269|PubMed:17079286, ECO:0000269|PubMed:18096616, CC ECO:0000269|PubMed:18835251, ECO:0000269|PubMed:19229320, CC ECO:0000269|PubMed:22801494, ECO:0000269|PubMed:23084476, CC ECO:0000269|PubMed:25740987, ECO:0000269|PubMed:26705305, CC ECO:0000269|PubMed:31246429, ECO:0000269|PubMed:8576172, CC ECO:0000269|PubMed:9079663, ECO:0000269|PubMed:9143277, CC ECO:0000269|PubMed:9781815}. CC -!- SUBUNIT: (Microbial infection) Interacts with human cytomegalovirus CC (HCMV) TRS1; this interaction retains EIF2AK2 to the nucleus and CC prevents its activation. {ECO:0000269|PubMed:16987971, CC ECO:0000269|PubMed:27780231}. CC -!- SUBUNIT: (Microbial infection) Interacts with vaccinia virus protein K3 CC (K3L); this interaction inhibits EIF2AK2. CC {ECO:0000269|PubMed:18971339}. CC -!- SUBUNIT: (Microbial infection) Interacts with human herpes simplex CC virus 1 (HHV-1) protein US11 in an RNA-dependent manner. CC {ECO:0000269|PubMed:11836380}. CC -!- SUBUNIT: (Microbial infection) The inactive form interacts with Toscana CC virus (TOS) NSS. {ECO:0000269|PubMed:23325696}. CC -!- SUBUNIT: (Microbial infection) Interacts with herpes virus 8 protein v- CC IRF2; this interaction inhibits EIF2AK2 activation. CC {ECO:0000269|PubMed:11160738}. CC -!- SUBUNIT: (Microbial infection) Interacts with vaccinia protein E3. CC {ECO:0000269|PubMed:25740987}. CC -!- SUBUNIT: (Microbial infection) Interacts (via N-terminus) with CC Hepatitis C virus (HCV) mature core protein (via N-terminus); this CC interaction induces the autophosphorylation of EIF2AK2. CC {ECO:0000269|PubMed:17267064}. CC -!- SUBUNIT: (Microbial infection) Interacts with Hepatitis C virus (HCV) CC non-structural protein 5A (NS5A); this interaction leads to disruption CC of EIF2AK2 dimerization by NS5A. {ECO:0000269|PubMed:16951545, CC ECO:0000269|PubMed:17451199, ECO:0000269|PubMed:9143277, CC ECO:0000269|PubMed:9710605}. CC -!- SUBUNIT: (Microbial infection) Interacts with Hepatitis C virus (HCV) CC envelope glycoprotein E2; this interaction inhibits EIF2AK2 and blocks CC its inhibitory effect on protein synthesis and cell growth. CC {ECO:0000269|PubMed:9143277}. CC -!- SUBUNIT: (Microbial infection) Interacts with human respiratory CC syncytial virus (HRSV) nucleoprotein; this interaction inhibits EIF2AK2 CC phosphorylation of EIF2S1 and blocks EIF2AK2-mediated translation CC shutoff. {ECO:0000269|PubMed:20519500}. CC -!- SUBUNIT: (Microbial infection) Interacts with human herpesvirus 8 CC protein MTA/ORF57; this interaction inhibits stress granule formation. CC {ECO:0000269|PubMed:29084250}. CC -!- INTERACTION: CC P19525; P78563-4: ADARB1; NbExp=3; IntAct=EBI-640775, EBI-12002366; CC P19525; P06493: CDK1; NbExp=4; IntAct=EBI-640775, EBI-444308; CC P19525; Q7L2E3: DHX30; NbExp=4; IntAct=EBI-640775, EBI-1211456; CC P19525; Q96C10: DHX58; NbExp=2; IntAct=EBI-640775, EBI-744193; CC P19525; Q08211: DHX9; NbExp=4; IntAct=EBI-640775, EBI-352022; CC P19525; Q9UPY3: DICER1; NbExp=2; IntAct=EBI-640775, EBI-395506; CC P19525; Q6P2E9: EDC4; NbExp=2; IntAct=EBI-640775, EBI-1006038; CC P19525; P19525: EIF2AK2; NbExp=2; IntAct=EBI-640775, EBI-640775; CC P19525; P05198: EIF2S1; NbExp=5; IntAct=EBI-640775, EBI-1056162; CC P19525; P56537: EIF6; NbExp=2; IntAct=EBI-640775, EBI-372243; CC P19525; Q8IY81: FTSJ3; NbExp=3; IntAct=EBI-640775, EBI-744088; CC P19525; Q9HCE1: MOV10; NbExp=3; IntAct=EBI-640775, EBI-1055820; CC P19525; Q96P20: NLRP3; NbExp=6; IntAct=EBI-640775, EBI-6253230; CC P19525; P06748: NPM1; NbExp=4; IntAct=EBI-640775, EBI-78579; CC P19525; O75569: PRKRA; NbExp=6; IntAct=EBI-640775, EBI-713955; CC P19525; O75569-1: PRKRA; NbExp=3; IntAct=EBI-640775, EBI-15588172; CC P19525; Q9NUL3: STAU2; NbExp=3; IntAct=EBI-640775, EBI-722938; CC P19525; Q15633: TARBP2; NbExp=2; IntAct=EBI-640775, EBI-978581; CC P19525; Q9H0E2: TOLLIP; NbExp=2; IntAct=EBI-640775, EBI-74615; CC P19525; Q9UL40: ZNF346; NbExp=4; IntAct=EBI-640775, EBI-2462313; CC P19525; Q27968: DNAJC3; Xeno; NbExp=5; IntAct=EBI-640775, EBI-640793; CC P19525; P0DTC9: N; Xeno; NbExp=8; IntAct=EBI-640775, EBI-25475856; CC P19525; P20639: OPG041; Xeno; NbExp=3; IntAct=EBI-640775, EBI-8674942; CC P19525; P04487: US11; Xeno; NbExp=3; IntAct=EBI-640775, EBI-6150681; CC P19525; Q2HR71: vIRF-2; Xeno; NbExp=2; IntAct=EBI-640775, EBI-8876177; CC P19525; PRO_0000278746 [O92972]; Xeno; NbExp=2; IntAct=EBI-640775, EBI-6918883; CC P19525; PRO_0000037570 [P27958]; Xeno; NbExp=4; IntAct=EBI-640775, EBI-6904269; CC P19525; PRO_0000037576 [P27958]; Xeno; NbExp=5; IntAct=EBI-640775, EBI-8753518; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15121867, CC ECO:0000269|PubMed:21029237, ECO:0000269|PubMed:22214662, CC ECO:0000269|PubMed:26705305}. Nucleus {ECO:0000269|PubMed:21029237, CC ECO:0000269|PubMed:21072047, ECO:0000269|PubMed:26705305}. Cytoplasm, CC perinuclear region {ECO:0000269|PubMed:15121867}. Note=Nuclear CC localization is elevated in acute leukemia, myelodysplastic syndrome CC (MDS), melanoma, breast, colon, prostate and lung cancer patient CC samples or cell lines as well as neurocytes from advanced Creutzfeldt- CC Jakob disease patients. {ECO:0000269|PubMed:21072047}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P19525-1; Sequence=Displayed; CC Name=2; CC IsoId=P19525-2; Sequence=VSP_046177; CC -!- TISSUE SPECIFICITY: Highly expressed in thymus, spleen and bone marrow CC compared to non-hematopoietic tissues such as small intestine, liver, CC or kidney tissues. Colocalizes with GSK3B and TAU in the Alzheimer CC disease (AD) brain. Elevated levels seen in breast and colon CC carcinomas, and which correlates with tumor progression and CC invasiveness or risk of progression. {ECO:0000269|PubMed:21029237, CC ECO:0000269|PubMed:23403623}. CC -!- INDUCTION: By type I interferons. {ECO:0000269|PubMed:1695551}. CC -!- DOMAIN: Contains 2 dsRNA-binding domain (DRBM) (PubMed:9736623). The N- CC terminus contains the catalytic domain dimerization. The C-terminus CC binds EIF2S1/EIF2-alpha (PubMed:16179258). CC {ECO:0000269|PubMed:16179258, ECO:0000269|PubMed:9736623}. CC -!- PTM: Autophosphorylated on several Ser, Thr and Tyr residues. CC Autophosphorylation of Thr-451 is dependent on Thr-446 and is CC stimulated by dsRNA binding and dimerization. Autophosphorylation CC apparently leads to the activation of the kinase. Tyrosine CC autophosphorylation is essential for efficient dsRNA-binding, CC dimerization, and kinase activation. Autophosphorylation is inhibited CC by the concerted action of ATAC complex subunit MBIP and molybdopterin CC synthase complex subunit MOCS2B (PubMed:26705305). CC {ECO:0000269|PubMed:11152499, ECO:0000269|PubMed:11337501, CC ECO:0000269|PubMed:16179258, ECO:0000269|PubMed:16373505, CC ECO:0000269|PubMed:20685959, ECO:0000269|PubMed:21029237, CC ECO:0000269|PubMed:21072047, ECO:0000269|PubMed:26705305}. CC -!- DISEASE: Leukoencephalopathy, developmental delay, and episodic CC neurologic regression syndrome (LEUDEN) [MIM:618877]: An autosomal CC dominant disorder characterized by global developmental delay apparent CC in early childhood, cognitive impairment, ataxia, poor or absent speech CC with dysarthria, hypotonia, hypertonia, extrapyramidal signs, tremor, CC and abnormal involuntary movements. Affected individuals also exhibit CC neurological regression in the setting of febrile illness or infection. CC Many patients have seizures. Brain imaging shows diffuse white matter CC abnormalities with poor myelination. {ECO:0000269|PubMed:32197074}. CC Note=The disease may be caused by variants affecting the gene CC represented in this entry. CC -!- DISEASE: Dystonia 33 (DYT33) [MIM:619687]: A form of dystonia, a CC disorder defined by the presence of sustained involuntary muscle CC contraction, often leading to abnormal postures. DYT33 is a slowly CC progressive form characterized by onset of focal or generalized CC dystonia in the first decades of life. Disease manifestations are CC variable. Some patients show ambulation difficulties, dysarthria, or CC dysphagia. Some affected individuals may manifest motor delay, lower CC limb spasticity, and mild developmental delay with intellectual CC disability. DYT33 penetrance is incomplete. Inheritance can be CC autosomal dominant or recessive. {ECO:0000269|PubMed:33236446, CC ECO:0000269|PubMed:33866603, ECO:0000269|PubMed:35146068}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein CC kinase family. GCN2 subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/41866/EIF2AK2"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M35663; AAA36409.1; -; mRNA. DR EMBL; M85294; AAA18253.1; -; mRNA. DR EMBL; U50648; AAC50768.1; -; Genomic_DNA. DR EMBL; U50634; AAC50768.1; JOINED; Genomic_DNA. DR EMBL; U50635; AAC50768.1; JOINED; Genomic_DNA. DR EMBL; U50636; AAC50768.1; JOINED; Genomic_DNA. DR EMBL; U50637; AAC50768.1; JOINED; Genomic_DNA. DR EMBL; U50638; AAC50768.1; JOINED; Genomic_DNA. DR EMBL; U50639; AAC50768.1; JOINED; Genomic_DNA. DR EMBL; U50640; AAC50768.1; JOINED; Genomic_DNA. DR EMBL; U50641; AAC50768.1; JOINED; Genomic_DNA. DR EMBL; U50642; AAC50768.1; JOINED; Genomic_DNA. DR EMBL; U50643; AAC50768.1; JOINED; Genomic_DNA. DR EMBL; U50644; AAC50768.1; JOINED; Genomic_DNA. DR EMBL; U50645; AAC50768.1; JOINED; Genomic_DNA. DR EMBL; U50646; AAC50768.1; JOINED; Genomic_DNA. DR EMBL; U50647; AAC50768.1; JOINED; Genomic_DNA. DR EMBL; AF167472; AAF13156.1; -; Genomic_DNA. DR EMBL; AF167460; AAF13156.1; JOINED; Genomic_DNA. DR EMBL; AF167462; AAF13156.1; JOINED; Genomic_DNA. DR EMBL; AF167463; AAF13156.1; JOINED; Genomic_DNA. DR EMBL; AF167464; AAF13156.1; JOINED; Genomic_DNA. DR EMBL; AF167465; AAF13156.1; JOINED; Genomic_DNA. DR EMBL; AF167466; AAF13156.1; JOINED; Genomic_DNA. DR EMBL; AF167468; AAF13156.1; JOINED; Genomic_DNA. DR EMBL; AF167470; AAF13156.1; JOINED; Genomic_DNA. DR EMBL; AY302136; AAP57628.1; -; mRNA. DR EMBL; AK290655; BAF83344.1; -; mRNA. DR EMBL; AK313818; BAG36554.1; -; mRNA. DR EMBL; AY228338; AAO38055.1; -; Genomic_DNA. DR EMBL; AC007899; AAY24317.1; -; Genomic_DNA. DR EMBL; CH471053; EAX00407.1; -; Genomic_DNA. DR EMBL; CH471053; EAX00408.1; -; Genomic_DNA. DR EMBL; CH471053; EAX00409.1; -; Genomic_DNA. DR EMBL; BC093676; AAH93676.1; -; mRNA. DR EMBL; BC101475; AAI01476.1; -; mRNA. DR CCDS; CCDS1786.1; -. [P19525-1] DR CCDS; CCDS46259.1; -. [P19525-2] DR PIR; JC5225; JC5225. DR RefSeq; NP_001129123.1; NM_001135651.3. [P19525-1] DR RefSeq; NP_001129124.1; NM_001135652.2. [P19525-2] DR RefSeq; NP_002750.1; NM_002759.4. [P19525-1] DR RefSeq; XP_011531289.1; XM_011532987.3. [P19525-1] DR RefSeq; XP_054198993.1; XM_054343018.1. [P19525-1] DR PDB; 1QU6; NMR; -; A=1-170. DR PDB; 2A19; X-ray; 2.50 A; B/C=258-550. DR PDB; 2A1A; X-ray; 2.80 A; B=258-550. DR PDB; 3UIU; X-ray; 2.90 A; A/B=254-551. DR PDB; 6D3K; X-ray; 2.60 A; A/B/C=229-551. DR PDB; 6D3L; X-ray; 3.10 A; A=229-551. DR PDB; 7OBK; X-ray; 1.80 A; B=541-551. DR PDB; 7OBL; X-ray; 1.80 A; B=541-551. DR PDB; 8BI7; X-ray; 1.40 A; B=541-551. DR PDB; 8I9J; EM; 6.39 A; A=1-170. DR PDB; 8IZN; EM; 6.67 A; A=1-170. DR PDBsum; 1QU6; -. DR PDBsum; 2A19; -. DR PDBsum; 2A1A; -. DR PDBsum; 3UIU; -. DR PDBsum; 6D3K; -. DR PDBsum; 6D3L; -. DR PDBsum; 7OBK; -. DR PDBsum; 7OBL; -. DR PDBsum; 8BI7; -. DR PDBsum; 8I9J; -. DR PDBsum; 8IZN; -. DR AlphaFoldDB; P19525; -. DR BMRB; P19525; -. DR EMDB; EMD-35274; -. DR EMDB; EMD-35866; -. DR SMR; P19525; -. DR BioGRID; 111596; 395. DR DIP; DIP-2657N; -. DR FunCoup; P19525; 998. DR IntAct; P19525; 176. DR MINT; P19525; -. DR STRING; 9606.ENSP00000233057; -. DR BindingDB; P19525; -. DR ChEMBL; CHEMBL5785; -. DR DrugBank; DB12010; Fostamatinib. DR DrugBank; DB07995; H-89. DR DrugBank; DB00328; Indomethacin. DR DrugCentral; P19525; -. DR GuidetoPHARMACOLOGY; 2016; -. DR GlyGen; P19525; 2 sites, 1 N-linked glycan (1 site), 1 O-linked glycan (1 site). DR iPTMnet; P19525; -. DR PhosphoSitePlus; P19525; -. DR SwissPalm; P19525; -. DR BioMuta; EIF2AK2; -. DR DMDM; 125527; -. DR jPOST; P19525; -. DR MassIVE; P19525; -. DR PaxDb; 9606-ENSP00000233057; -. DR PeptideAtlas; P19525; -. DR ProteomicsDB; 19391; -. DR ProteomicsDB; 53670; -. [P19525-1] DR Pumba; P19525; -. DR TopDownProteomics; P19525-1; -. [P19525-1] DR Antibodypedia; 3548; 1196 antibodies from 44 providers. DR DNASU; 5610; -. DR Ensembl; ENST00000233057.9; ENSP00000233057.4; ENSG00000055332.20. [P19525-1] DR Ensembl; ENST00000395127.6; ENSP00000378559.2; ENSG00000055332.20. [P19525-1] DR Ensembl; ENST00000405334.5; ENSP00000385014.1; ENSG00000055332.20. [P19525-2] DR Ensembl; ENST00000647926.1; ENSP00000497534.1; ENSG00000055332.20. [P19525-1] DR Ensembl; ENST00000679507.1; ENSP00000506024.1; ENSG00000055332.20. [P19525-1] DR Ensembl; ENST00000681463.1; ENSP00000505138.1; ENSG00000055332.20. [P19525-1] DR Ensembl; ENST00000681507.1; ENSP00000505772.1; ENSG00000055332.20. [P19525-1] DR GeneID; 5610; -. DR KEGG; hsa:5610; -. DR MANE-Select; ENST00000233057.9; ENSP00000233057.4; NM_001135651.3; NP_001129123.1. DR UCSC; uc010fab.3; human. [P19525-1] DR AGR; HGNC:9437; -. DR ClinPGx; PA33779; -. DR CTD; 5610; -. DR DisGeNET; 5610; -. DR GeneCards; EIF2AK2; -. DR HGNC; HGNC:9437; EIF2AK2. DR HPA; ENSG00000055332; Low tissue specificity. DR MalaCards; EIF2AK2; -. DR MIM; 176871; gene. DR MIM; 618877; phenotype. DR MIM; 619687; phenotype. DR OpenTargets; ENSG00000055332; -. DR Orphanet; 256; Early-onset generalized limb-onset dystonia. DR VEuPathDB; HostDB:ENSG00000055332; -. DR eggNOG; KOG1033; Eukaryota. DR GeneTree; ENSGT00940000160736; -. DR HOGENOM; CLU_023682_1_0_1; -. DR InParanoid; P19525; -. DR OMA; KIACEMM; -. DR OrthoDB; 341578at2759; -. DR PAN-GO; P19525; 2 GO annotations based on evolutionary models. DR PhylomeDB; P19525; -. DR PathwayCommons; P19525; -. DR Reactome; R-HSA-1169408; ISG15 antiviral mechanism. DR Reactome; R-HSA-169131; Inhibition of PKR. DR Reactome; R-HSA-4755510; SUMOylation of immune response proteins. DR Reactome; R-HSA-909733; Interferon alpha/beta signaling. DR Reactome; R-HSA-9833109; Evasion by RSV of host interferon responses. DR Reactome; R-HSA-9833482; PKR-mediated signaling. DR SignaLink; P19525; -. DR SIGNOR; P19525; -. DR Agora; ENSG00000055332; -. DR BioGRID-ORCS; 5610; 13 hits in 1193 CRISPR screens. DR CD-CODE; 91857CE7; Nucleolus. DR CD-CODE; DEE660B4; Stress granule. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; EIF2AK2; human. DR EvolutionaryTrace; P19525; -. DR GeneWiki; Protein_kinase_R; -. DR GenomeRNAi; 5610; -. DR Pharos; P19525; Tchem. DR PRO; PR:P19525; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; P19525; protein. DR Bgee; ENSG00000055332; Expressed in endometrium epithelium and 211 other cell types or tissues. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0005840; C:ribosome; TAS:AgBase. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0003725; F:double-stranded RNA binding; IDA:MGI. DR GO; GO:0004694; F:eukaryotic translation initiation factor 2alpha kinase activity; IMP:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0016301; F:kinase activity; IDA:UniProt. DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IEA:UniProtKB-EC. DR GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB. DR GO; GO:0019888; F:protein phosphatase regulator activity; TAS:ProtInc. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProt. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0140374; P:antiviral innate immune response; IDA:UniProt. DR GO; GO:0034198; P:cellular response to amino acid starvation; IMP:UniProtKB. DR GO; GO:0051607; P:defense response to virus; IEP:ARUK-UCL. DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IEA:Ensembl. DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0008285; P:negative regulation of cell population proliferation; TAS:ProtInc. DR GO; GO:0033689; P:negative regulation of osteoblast proliferation; IMP:UniProtKB. DR GO; GO:0017148; P:negative regulation of translation; IDA:UniProtKB. DR GO; GO:0045071; P:negative regulation of viral genome replication; IMP:UniProtKB. DR GO; GO:0032722; P:positive regulation of chemokine production; ISS:UniProtKB. DR GO; GO:0001819; P:positive regulation of cytokine production; ISS:UniProtKB. DR GO; GO:0043410; P:positive regulation of MAPK cascade; IMP:UniProtKB. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:UniProtKB. DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; ISS:UniProtKB. DR GO; GO:0032874; P:positive regulation of stress-activated MAPK cascade; ISS:UniProtKB. DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB. DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB. DR GO; GO:1901532; P:regulation of hematopoietic progenitor cell differentiation; ISS:UniProtKB. DR GO; GO:1902036; P:regulation of hematopoietic stem cell differentiation; ISS:UniProtKB. DR GO; GO:1902033; P:regulation of hematopoietic stem cell proliferation; ISS:UniProtKB. DR GO; GO:1900225; P:regulation of NLRP3 inflammasome complex assembly; ISS:UniProtKB. DR GO; GO:0006446; P:regulation of translational initiation; IBA:GO_Central. DR GO; GO:0035455; P:response to interferon-alpha; IDA:UniProtKB. DR GO; GO:0009615; P:response to virus; IMP:UniProtKB. DR GO; GO:0006412; P:translation; IEA:Ensembl. DR CDD; cd19903; DSRM_EIF2AK2_rpt1; 1. DR CDD; cd19904; DSRM_EIF2AK2_rpt2; 1. DR CDD; cd14047; STKc_EIF2AK2_PKR; 1. DR DisProt; DP03944; -. DR FunFam; 3.30.160.20:FF:000045; Eukaryotic translation initiation factor 2-alpha kinase 2; 1. DR FunFam; 3.30.160.20:FF:000062; Eukaryotic translation initiation factor 2-alpha kinase 2; 1. DR FunFam; 3.30.200.20:FF:000536; Eukaryotic translation initiation factor 2-alpha kinase 2; 1. DR FunFam; 1.10.510.10:FF:000251; eukaryotic translation initiation factor 2-alpha kinase 3; 1. DR Gene3D; 3.30.160.20; -; 2. DR Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR IDEAL; IID00443; -. DR InterPro; IPR050339; CC_SR_Kinase. DR InterPro; IPR014720; dsRBD_dom. DR InterPro; IPR044452; EIF2AK2_DSRM_1. DR InterPro; IPR044453; EIF2AK2_DSRM_2. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR11042; EUKARYOTIC TRANSLATION INITIATION FACTOR 2-ALPHA KINASE EIF2-ALPHA KINASE -RELATED; 1. DR PANTHER; PTHR11042:SF163; INTERFERON-INDUCED, DOUBLE-STRANDED RNA-ACTIVATED PROTEIN KINASE; 1. DR Pfam; PF00035; dsrm; 2. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00358; DSRM; 2. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF54768; dsRNA-binding domain-like; 2. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS50137; DS_RBD; 2. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Antiviral defense; KW ATP-binding; Cytoplasm; Direct protein sequencing; Disease variant; KW Dystonia; Host-virus interaction; Immunity; Innate immunity; KW Isopeptide bond; Kinase; Magnesium; Nucleotide-binding; Nucleus; KW Phosphoprotein; Proteomics identification; Reference proteome; Repeat; KW RNA-binding; Serine/threonine-protein kinase; Transcription; KW Transcription regulation; Transferase; Tyrosine-protein kinase; KW Ubl conjugation. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000269|Ref.13, ECO:0007744|PubMed:22223895, FT ECO:0007744|PubMed:22814378" FT CHAIN 2..551 FT /note="Interferon-induced, double-stranded RNA-activated FT protein kinase" FT /id="PRO_0000085945" FT DOMAIN 9..77 FT /note="DRBM 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00266, FT ECO:0000269|PubMed:9736623" FT DOMAIN 100..167 FT /note="DRBM 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00266, FT ECO:0000269|PubMed:9736623" FT DOMAIN 267..538 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REPEAT 331..343 FT /note="1" FT REPEAT 345..357 FT /note="2" FT REGION 2..180 FT /note="(Microbial infection) Interaction with HCV NS5A" FT /evidence="ECO:0000269|PubMed:17267064" FT REGION 202..222 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 266..551 FT /note="Interaction with TRAF5" FT /evidence="ECO:0000269|PubMed:15121867" FT REGION 266..362 FT /note="Dimerization" FT /evidence="ECO:0000269|PubMed:16179258" FT REGION 331..357 FT /note="2 X 13 AA approximate repeats" FT REGION 379..496 FT /note="Interaction with EIF2S1/EIF-2ALPHA" FT /evidence="ECO:0000269|PubMed:16179258" FT COMPBIAS 202..215 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 414 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 273..281 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 296 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT BINDING 432 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000305|PubMed:16179258, FT ECO:0000305|PubMed:31246429" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0000269|Ref.13, ECO:0007744|PubMed:22223895, FT ECO:0007744|PubMed:22814378" FT MOD_RES 83 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:11152499, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:19690332, FT ECO:0007744|PubMed:20068231" FT MOD_RES 88 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000305|PubMed:11152499" FT MOD_RES 89 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000305|PubMed:11152499" FT MOD_RES 90 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000305|PubMed:11152499" FT MOD_RES 101 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:16373505" FT MOD_RES 162 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:16373505" FT MOD_RES 242 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000305|PubMed:11152499" FT MOD_RES 255 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000305|PubMed:11152499" FT MOD_RES 258 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000305|PubMed:11152499" FT MOD_RES 293 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:16373505" FT MOD_RES 446 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:11337501, FT ECO:0000269|PubMed:16179258" FT MOD_RES 451 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:11337501, FT ECO:0000269|PubMed:20685959" FT MOD_RES 456 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 542 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT CROSSLNK 69 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ISG15)" FT /evidence="ECO:0000269|PubMed:23229543" FT CROSSLNK 159 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ISG15)" FT /evidence="ECO:0000269|PubMed:23229543" FT VAR_SEQ 263..303 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|Ref.7" FT /id="VSP_046177" FT VARIANT 11 FT /note="M -> L (in LEUDEN; uncertain significance; reduced FT phosphorylation of eukaryotic translation initiation factor FT 2-alpha in patient cells)" FT /evidence="ECO:0000269|PubMed:32197074" FT /id="VAR_084260" FT VARIANT 32 FT /note="N -> S (in LEUDEN; uncertain significance)" FT /evidence="ECO:0000269|PubMed:32197074" FT /id="VAR_084261" FT VARIANT 32 FT /note="N -> T (in DYT33; uncertain significance; gain-of- FT function variant resulting in increased levels of FT phosphorylated EIF2AK2 and EIF2A in patient cells compared FT to controls)" FT /evidence="ECO:0000269|PubMed:33236446" FT /id="VAR_086715" FT VARIANT 97 FT /note="S -> F (in LEUDEN; uncertain significance)" FT /evidence="ECO:0000269|PubMed:32197074" FT /id="VAR_084262" FT VARIANT 109 FT /note="A -> S (in LEUDEN; uncertain significance)" FT /evidence="ECO:0000269|PubMed:32197074" FT /id="VAR_084263" FT VARIANT 109 FT /note="A -> V (in LEUDEN; uncertain significance)" FT /evidence="ECO:0000269|PubMed:32197074" FT /id="VAR_084264" FT VARIANT 114 FT /note="L -> Q (found in a patient with dysmorphic facies, FT syndactyly, congenital microcephaly and global FT developmental delay; uncertain significance)" FT /evidence="ECO:0000269|PubMed:32197074" FT /id="VAR_084265" FT VARIANT 130 FT /note="G -> R (in DYT33; gain-of-function variant resulting FT in increased levels of phosphorylated EIF2AK2 and EIF2A in FT patient cells compared to controls)" FT /evidence="ECO:0000269|PubMed:33236446, FT ECO:0000269|PubMed:33866603, ECO:0000269|PubMed:35146068" FT /id="VAR_086716" FT VARIANT 133 FT /note="Y -> F (in LEUDEN; uncertain significance; reduced FT phosphorylation of eukaryotic translation initiation factor FT 2-alpha in patient cells)" FT /evidence="ECO:0000269|PubMed:32197074" FT /id="VAR_084266" FT VARIANT 138 FT /note="G -> A (in DYT33; uncertain significance)" FT /evidence="ECO:0000269|PubMed:33236446" FT /id="VAR_086717" FT VARIANT 325 FT /note="G -> S (in LEUDEN; uncertain significance)" FT /evidence="ECO:0000269|PubMed:32197074" FT /id="VAR_084267" FT VARIANT 428 FT /note="V -> E (in dbSNP:rs56219559)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040474" FT VARIANT 439 FT /note="L -> V (in a lung adenocarcinoma sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040475" FT VARIANT 461 FT /note="S -> C (in LEUDEN; uncertain significance; reduced FT phosphorylation of eukaryotic translation initiation factor FT 2-alpha in patient cells)" FT /evidence="ECO:0000269|PubMed:32197074" FT /id="VAR_084268" FT VARIANT 506 FT /note="I -> V (no effect on PKR inhibition by HCMV protein FT TRS1; dbSNP:rs34821155)" FT /evidence="ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:27780231" FT /id="VAR_040476" FT MUTAGEN 59..60 FT /note="SK->AA: In FL-PKR-2AI; moderate loss of activity but FT no effect on dsRNA binding." FT /evidence="ECO:0000269|PubMed:11337501" FT MUTAGEN 60 FT /note="K->A: Impairs dsRNA binding but not dimerization or FT activity." FT /evidence="ECO:0000269|PubMed:11337501" FT MUTAGEN 67 FT /note="A->E: Significant loss of activity; loss of dsRNA FT binding and dimerization." FT /evidence="ECO:0000269|PubMed:11337501" FT MUTAGEN 83 FT /note="S->A: No effect on enzymatic activity; when FT associated with A-88; A-89 and A-90." FT /evidence="ECO:0000269|PubMed:11152499" FT MUTAGEN 88 FT /note="T->A: No effect on enzymatic activity; when FT associated with A-83; A-89 and A-90." FT /evidence="ECO:0000269|PubMed:11152499" FT MUTAGEN 89 FT /note="T->A: No effect on enzymatic activity; when FT associated with A-83; A-88 and A-90." FT /evidence="ECO:0000269|PubMed:11152499" FT MUTAGEN 90 FT /note="T->A: No effect on enzymatic activity; when FT associated with A-83; A-88 and A-89." FT /evidence="ECO:0000269|PubMed:11152499" FT MUTAGEN 149..150 FT /note="TK->AA: In FL-PKR-2AII; no effect on activity." FT /evidence="ECO:0000269|PubMed:11337501" FT MUTAGEN 242 FT /note="S->A: Moderate loss of activity; when associated FT with A-255 and A-258." FT /evidence="ECO:0000269|PubMed:11152499" FT MUTAGEN 244..296 FT /note="Missing: Loss of activity." FT /evidence="ECO:0000269|PubMed:11337501" FT MUTAGEN 255 FT /note="T->A: Moderate loss of activity; when associated FT with A-242 and A-255." FT /evidence="ECO:0000269|PubMed:11152499" FT MUTAGEN 258 FT /note="T->A: Moderate loss of activity." FT /evidence="ECO:0000269|PubMed:11152499" FT MUTAGEN 296 FT /note="K->R: Loss of activity." FT /evidence="ECO:0000269|PubMed:11152499" FT MUTAGEN 446 FT /note="T->A: Significant loss of activity and impairs FT autophosphorylation of T-451." FT /evidence="ECO:0000269|PubMed:11337501" FT MUTAGEN 451 FT /note="T->A: Loss of activity." FT /evidence="ECO:0000269|PubMed:11337501" FT MUTAGEN 486 FT /note="D->V: 15-fold decrease in K3L binding affinity and FT thus resistance of mutated PKR to K3L inhibition." FT /evidence="ECO:0000269|PubMed:18971339" FT MUTAGEN 489 FT /note="F->S: Loss of PKR inhibition by HCMV protein TRS1." FT /evidence="ECO:0000269|PubMed:27780231" FT MUTAGEN 496 FT /note="T->K: No effect on PKR inhibition by HCMV protein FT TRS1." FT /evidence="ECO:0000269|PubMed:27780231" FT MUTAGEN 502 FT /note="I->T: No effect on PKR inhibition by HCMV protein FT TRS1." FT /evidence="ECO:0000269|PubMed:27780231" FT MUTAGEN 510 FT /note="K->R: No effect on PKR inhibition by HCMV protein FT TRS1." FT /evidence="ECO:0000269|PubMed:27780231" FT MUTAGEN 516 FT /note="Q->E: No effect on PKR inhibition by HCMV protein FT TRS1." FT /evidence="ECO:0000269|PubMed:27780231" FT CONFLICT 102 FT /note="I -> M (in Ref. 7; AAP57628)" FT /evidence="ECO:0000305" FT CONFLICT 224 FT /note="S -> R (in Ref. 7; AAP57628)" FT /evidence="ECO:0000305" FT CONFLICT 512 FT /note="K -> E (in Ref. 6; AAF13156)" FT /evidence="ECO:0000305" FT STRAND 5..7 FT /evidence="ECO:0007829|PDB:1QU6" FT HELIX 10..21 FT /evidence="ECO:0007829|PDB:1QU6" FT STRAND 26..32 FT /evidence="ECO:0007829|PDB:1QU6" FT TURN 35..37 FT /evidence="ECO:0007829|PDB:1QU6" FT STRAND 41..50 FT /evidence="ECO:0007829|PDB:1QU6" FT STRAND 54..56 FT /evidence="ECO:0007829|PDB:1QU6" FT HELIX 61..76 FT /evidence="ECO:0007829|PDB:1QU6" FT HELIX 102..111 FT /evidence="ECO:0007829|PDB:1QU6" FT STRAND 115..123 FT /evidence="ECO:0007829|PDB:1QU6" FT STRAND 125..138 FT /evidence="ECO:0007829|PDB:1QU6" FT STRAND 144..149 FT /evidence="ECO:0007829|PDB:1QU6" FT HELIX 150..167 FT /evidence="ECO:0007829|PDB:1QU6" FT HELIX 261..266 FT /evidence="ECO:0007829|PDB:2A19" FT STRAND 267..274 FT /evidence="ECO:0007829|PDB:2A19" FT STRAND 276..278 FT /evidence="ECO:0007829|PDB:2A19" FT STRAND 281..286 FT /evidence="ECO:0007829|PDB:2A19" FT TURN 287..289 FT /evidence="ECO:0007829|PDB:2A19" FT STRAND 292..299 FT /evidence="ECO:0007829|PDB:2A19" FT HELIX 303..305 FT /evidence="ECO:0007829|PDB:2A19" FT HELIX 306..314 FT /evidence="ECO:0007829|PDB:2A19" FT STRAND 323..332 FT /evidence="ECO:0007829|PDB:2A19" FT STRAND 358..366 FT /evidence="ECO:0007829|PDB:2A19" FT HELIX 374..380 FT /evidence="ECO:0007829|PDB:2A19" FT HELIX 381..383 FT /evidence="ECO:0007829|PDB:2A19" FT HELIX 388..407 FT /evidence="ECO:0007829|PDB:2A19" FT STRAND 410..412 FT /evidence="ECO:0007829|PDB:2A1A" FT HELIX 417..419 FT /evidence="ECO:0007829|PDB:2A19" FT STRAND 420..424 FT /evidence="ECO:0007829|PDB:2A19" FT STRAND 427..430 FT /evidence="ECO:0007829|PDB:2A19" FT HELIX 433..435 FT /evidence="ECO:0007829|PDB:6D3L" FT STRAND 437..440 FT /evidence="ECO:0007829|PDB:2A19" FT HELIX 457..461 FT /evidence="ECO:0007829|PDB:2A19" FT HELIX 468..482 FT /evidence="ECO:0007829|PDB:2A19" FT HELIX 488..499 FT /evidence="ECO:0007829|PDB:2A19" FT STRAND 505..507 FT /evidence="ECO:0007829|PDB:3UIU" FT HELIX 509..518 FT /evidence="ECO:0007829|PDB:2A19" FT HELIX 523..525 FT /evidence="ECO:0007829|PDB:2A19" FT HELIX 529..539 FT /evidence="ECO:0007829|PDB:2A19" SQ SEQUENCE 551 AA; 62094 MW; 815AD83ACAB45DA3 CRC64; MAGDLSAGFF MEELNTYRQK QGVVLKYQEL PNSGPPHDRR FTFQVIIDGR EFPEGEGRSK KEAKNAAAKL AVEILNKEKK AVSPLLLTTT NSSEGLSMGN YIGLINRIAQ KKRLTVNYEQ CASGVHGPEG FHYKCKMGQK EYSIGTGSTK QEAKQLAAKL AYLQILSEET SVKSDYLSSG SFATTCESQS NSLVTSTLAS ESSSEGDFSA DTSEINSNSD SLNSSSLLMN GLRNNQRKAK RSLAPRFDLP DMKETKYTVD KRFGMDFKEI ELIGSGGFGQ VFKAKHRIDG KTYVIKRVKY NNEKAEREVK ALAKLDHVNI VHYNGCWDGF DYDPETSDDS LESSDYDPEN SKNSSRSKTK CLFIQMEFCD KGTLEQWIEK RRGEKLDKVL ALELFEQITK GVDYIHSKKL IHRDLKPSNI FLVDTKQVKI GDFGLVTSLK NDGKRTRSKG TLRYMSPEQI SSQDYGKEVD LYALGLILAE LLHVCDTAFE TSKFFTDLRD GIISDIFDKK EKTLLQKLLS KKPEDRPNTS EILRTLTVWK KSPEKNERHT C // ID FLNB_HUMAN Reviewed; 2602 AA. AC O75369; B2ZZ83; B2ZZ84; B2ZZ85; C9JKE6; C9JMC4; Q13706; Q59EC2; Q60FE7; AC Q6MZJ1; Q8WXS9; Q8WXT0; Q8WXT1; Q8WXT2; Q8WXT3; Q9NRB5; Q9NT26; Q9UEV9; DT 07-NOV-2003, integrated into UniProtKB/Swiss-Prot. DT 18-MAY-2010, sequence version 2. DT 28-JAN-2026, entry version 247. DE RecName: Full=Filamin-B; DE Short=FLN-B; DE AltName: Full=ABP-278; DE AltName: Full=ABP-280 homolog; DE AltName: Full=Actin-binding-like protein; DE AltName: Full=Beta-filamin; DE AltName: Full=Filamin homolog 1; DE Short=Fh1; DE AltName: Full=Filamin-3; DE AltName: Full=Thyroid autoantigen; DE AltName: Full=Truncated actin-binding protein; DE Short=Truncated ABP; GN Name=FLNB; Synonyms=FLN1L, FLN3, TABP, TAP; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, SUBCELLULAR RP LOCATION, INTERACTION WITH GP1BA, AND VARIANTS ASN-1157 AND MET-1471. RC TISSUE=Endothelial cell, and Placenta; RX PubMed=9651345; DOI=10.1074/jbc.273.28.17531; RA Takafuta T., Wu G., Murphy G.F., Shapiro S.S.; RT "Human beta-filamin is a new protein that interacts with the cytoplasmic RT tail of glycoprotein Ibalpha."; RL J. Biol. Chem. 273:17531-17538(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), ALTERNATIVE SPLICING, TISSUE RP SPECIFICITY, AND INTERACTION WITH GP1BA. RC TISSUE=Placenta; RX PubMed=9694715; RA Xu W.-F., Xie Z.-W., Chung D.W., Davie E.W.; RT "A novel human actin-binding protein homologue that binds to platelet RT glycoprotein Ibalpha."; RL Blood 92:1268-1276(1998). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1; 3; 4 AND 5), TISSUE RP SPECIFICITY, SUBCELLULAR LOCATION, AND INTERACTION WITH ISOFORMS OF ITGB1. RC TISSUE=Keratinocyte, and Skeletal muscle; RX PubMed=11807098; DOI=10.1083/jcb.200103037; RA van Der Flier A., Kuikman I., Kramer D., Geerts D., Kreft M., Takafuta T., RA Shapiro S.S., Sonnenberg A.; RT "Different splice variants of filamin-B affect myogenesis, subcellular RT distribution, and determine binding to integrin (beta) subunits."; RL J. Cell Biol. 156:361-376(2002). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), GENE ORGANIZATION, RP SIMILARITY TO OTHER MEMBERS OF THE FAMILY, AND VARIANTS ASN-1157 AND RP MET-1471. RX PubMed=11153914; DOI=10.1007/s004390000414; RA Chakarova C., Wehnert M.S., Uhl K., Sakthivel S., Vosberg H.-P., RA van der Ven P.F.M., Fuerst D.O.; RT "Genomic structure and fine mapping of the two human filamin gene RT paralogues FLNB and FLNC and comparative analysis of the filamin gene RT family."; RL Hum. Genet. 107:597-611(2000). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 8 AND 9), AND VARIANTS ASN-1157 RP AND MET-1471. RX PubMed=18487259; DOI=10.1093/dnares/dsn010; RA Oshikawa M., Sugai Y., Usami R., Ohtoko K., Toyama S., Kato S.; RT "Fine expression profiling of full-length transcripts using a size-unbiased RT cDNA library prepared with the vector-capping method."; RL DNA Res. 15:123-136(2008). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2; 8 AND 9). RX PubMed=16106752; DOI=10.1093/dnares/12.1.53; RA Kato S., Ohtoko K., Ohtake H., Kimura T.; RT "Vector-capping: a simple method for preparing a high-quality full-length RT cDNA library."; RL DNA Res. 12:53-62(2005). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 7). RC TISSUE=Endometrial tumor, and Fetal brain; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16641997; DOI=10.1038/nature04728; RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J., RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L., RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G., RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W., RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P., RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H., RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B., RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H., RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J., RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X., RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R., RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.; RT "The DNA sequence, annotation and analysis of human chromosome 3."; RL Nature 440:1194-1198(2006). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 990-2602. RC TISSUE=Aortic endothelium; RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., RA Ohara O., Nagase T., Kikuno R.F.; RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [MRNA] OF 2130-2602, AND INTERACTION WITH INPPL1. RC TISSUE=Skeletal muscle; RX PubMed=11739414; DOI=10.1083/jcb.200104005; RA Dyson J.M., O'Malley C.J., Becanovic J., Munday A.D., Berndt M.C., RA Coghill I.D., Nandurkar H.H., Ooms L.M., Mitchell C.A.; RT "The SH2-containing inositol polyphosphate 5-phosphatase, SHIP-2, binds RT filamin and regulates submembraneous actin."; RL J. Cell Biol. 155:1065-1079(2001). RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1874-2602. RC TISSUE=Fetal brain; RX PubMed=11230166; DOI=10.1101/gr.gr1547r; RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S., RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J., RA Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W., RA Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B., RA Klein M., Poustka A.; RT "Towards a catalog of human genes and proteins: sequencing and analysis of RT 500 novel complete protein coding human cDNAs."; RL Genome Res. 11:422-435(2001). RN [12] RP NUCLEOTIDE SEQUENCE [MRNA] OF 2311-2602, AND INTERACTION WITH PSEN1 AND RP PSEN2. RC TISSUE=Fetal brain; RX PubMed=9437013; DOI=10.1523/jneurosci.18-03-00914.1998; RA Zhang W., Han S.W., McKeel D.W., Goate A., Wu J.Y.; RT "Interaction of presenilins with the filamin family of actin-binding RT proteins."; RL J. Neurosci. 18:914-922(1998). RN [13] RP NUCLEOTIDE SEQUENCE [MRNA] OF 2404-2602, AND TISSUE SPECIFICITY. RC TISSUE=Thyroid; RX PubMed=8327473; DOI=10.1073/pnas.90.13.5994; RA Leedman P.J., Faulkner-Jones B., Cram D.C., Harrison P.J., West J., RA O'Brien E.J., Simpson R., Coppel R.L., Harrison L.C.; RT "Cloning from the thyroid of a protein related to actin binding protein RT that is recognized by Graves disease immunoglobulins."; RL Proc. Natl. Acad. Sci. U.S.A. 90:5994-5998(1993). RN [14] RP INTERACTION WITH HBV CAPSID PROTEIN. RX PubMed=10754391; DOI=10.1007/bf02256623; RA Huang C.J., Chen Y.H., Ting L.P.; RT "Hepatitis B virus core protein interacts with the C-terminal region of RT actin-binding protein."; RL J. Biomed. Sci. 7:160-168(2000). RN [15] RP INTERACTION WITH FLNA. RX PubMed=12393796; DOI=10.1093/hmg/11.23.2845; RA Sheen V.L., Feng Y., Graham D., Takafuta T., Shapiro S.S., Walsh C.A.; RT "Filamin A and filamin B are co-expressed within neurons during periods of RT neuronal migration and can physically interact."; RL Hum. Mol. Genet. 11:2845-2854(2002). RN [16] RP INTERACTION WITH FBLP1. RC TISSUE=Placenta; RX PubMed=12496242; DOI=10.1074/jbc.m209339200; RA Takafuta T., Saeki M., Fujimoto T.-T., Fujimura K., Shapiro S.S.; RT "A new member of the LIM protein family binds to filamin B and localizes at RT stress fibers."; RL J. Biol. Chem. 278:12175-12181(2003). RN [17] RP DIMERIZATION, AND INTERACTION WITH FLNC. RX PubMed=12525170; DOI=10.1021/bi026501+; RA Himmel M., van der Ven P.F.M., Stoecklein W., Fuerst D.O.; RT "The limits of promiscuity: isoform-specific dimerization of filamins."; RL Biochemistry 42:430-439(2003). RN [18] RP IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Lymphoblast; RX PubMed=14654843; DOI=10.1038/nature02166; RA Andersen J.S., Wilkinson C.J., Mayor T., Mortensen P., Nigg E.A., Mann M.; RT "Proteomic characterization of the human centrosome by protein correlation RT profiling."; RL Nature 426:570-574(2003). RN [19] RP INTERACTION WITH ITGB1; MYOT AND MYOZ1. RX PubMed=16076904; DOI=10.1242/jcs.02484; RA Gontier Y., Taivainen A., Fontao L., Sonnenberg A., van der Flier A., RA Carpen O., Faulkner G., Borradori L.; RT "The Z-disc proteins myotilin and FATZ-1 interact with each other and are RT connected to the sarcolemma via muscle-specific filamins."; RL J. Cell Sci. 118:3739-3749(2005). RN [20] RP REVIEW. RX PubMed=11336782; DOI=10.1016/s0167-4889(01)00072-6; RA van der Flier A., Sonnenberg A.; RT "Structural and functional aspects of filamins."; RL Biochim. Biophys. Acta 1538:99-117(2001). RN [21] RP REVIEW. RX PubMed=11252955; DOI=10.1038/35052082; RA Stossel T.P., Condeelis J., Cooley L., Hartwig J.H., Noegel A., RA Schleicher M., Shapiro S.S.; RT "Filamins as integrators of cell mechanics and signalling."; RL Nat. Rev. Mol. Cell Biol. 2:138-145(2001). RN [22] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-983, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=16964243; DOI=10.1038/nbt1240; RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.; RT "A probability-based approach for high-throughput protein phosphorylation RT analysis and site localization."; RL Nat. Biotechnol. 24:1285-1292(2006). RN [23] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [24] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-519; SER-983; SER-1028; RP SER-1316; SER-1505; SER-1602; SER-2083; SER-2107; SER-2478 AND SER-2481, RP AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [25] RP UBIQUITINATION. RX PubMed=19300455; DOI=10.1038/cdd.2009.27; RA Bello N.F., Lamsoul I., Heuze M.L., Metais A., Moreaux G., Calderwood D.A., RA Duprez D., Moog-Lutz C., Lutz P.G.; RT "The E3 ubiquitin ligase specificity subunit ASB2beta is a novel regulator RT of muscle differentiation that targets filamin B to proteasomal RT degradation."; RL Cell Death Differ. 16:921-932(2009). RN [26] RP ISGYLATION AT LYS-2468, AND MUTAGENESIS OF LYS-2468. RX PubMed=19270716; DOI=10.1038/embor.2009.23; RA Jeon Y.J., Choi J.S., Lee J.Y., Yu K.R., Kim S.M., Ka S.H., Oh K.H., RA Kim K.I., Zhang D.E., Bang O.S., Chung C.H.; RT "ISG15 modification of filamin B negatively regulates the type I RT interferon-induced JNK signalling pathway."; RL EMBO Rep. 10:374-380(2009). RN [27] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-983 AND SER-2478, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [28] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-681 AND LYS-2576, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [29] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-519; SER-730; SER-886; RP SER-932; SER-983; SER-1316; SER-1433; SER-2369; SER-2465 AND SER-2478, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [30] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [31] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [32] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [33] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-983; SER-1433; SER-1505; RP SER-2083; SER-2107; SER-2465; SER-2478 AND SER-2481, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [34] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-216; THR-1307; SER-1316; RP SER-2107; SER-2113 AND SER-2492, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT RP SER-1474 (ISOFORM 8), AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [35] RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 2-242. RX PubMed=19505475; DOI=10.1016/j.jmb.2009.06.009; RA Sawyer G.M., Clark A.R., Robertson S.P., Sutherland-Smith A.J.; RT "Disease-associated substitutions in the filamin B actin binding domain RT confer enhanced actin binding affinity in the absence of major structural RT disturbance: Insights from the crystal structures of filamin B actin RT binding domains."; RL J. Mol. Biol. 390:1030-1047(2009). RN [36] RP STRUCTURE BY NMR OF 1017-1721; 1736-2488 AND 2509-2602. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of the 9th through 24th filamin domains from human RT filamin-B."; RL Submitted (FEB-2009) to the PDB data bank. RN [37] RP INVOLVEMENT IN SCT, VARIANTS LRS CYS-161; LYS-227; ASN-1571 DEL; ARG-1586 RP AND SER-1691, VARIANTS AO1 VAL-173 AND PRO-188, VARIANT AO3 ARG-751, AND RP VARIANT AO1/AO3 VAL-202. RX PubMed=14991055; DOI=10.1038/ng1319; RA Krakow D., Robertson S.P., King L.M., Morgan T., Sebald E.T., RA Bertolotto C., Wachsmann-Hogiu S., Acuna D., Shapiro S.S., Takafuta T., RA Aftimos S., Kim C.A., Firth H., Steiner C.E., Cormier-Daire V., RA Superti-Furga A., Bonafe L., Graham J.M. Jr., Grix A., Bacino C.A., RA Allanson J., Bialer M.G., Lachman R.S., Rimoin D.L., Cohn D.H.; RT "Mutations in the gene encoding filamin B disrupt vertebral segmentation, RT joint formation and skeletogenesis."; RL Nat. Genet. 36:405-410(2004). RN [38] RP STRUCTURE BY NMR OF 1017-2602. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of filamin domains from human filamin-B."; RL Submitted (AUG-2007) to the PDB data bank. RN [39] RP VARIANTS BOOMD ARG-171 AND PRO-235. RX PubMed=15994868; DOI=10.1136/jmg.2004.029967; RA Bicknell L.S., Morgan T., Bonafe L., Wessels M.W., Bialer M.G., RA Willems P.J., Cohn D.H., Krakow D., Robertson S.P.; RT "Mutations in FLNB cause boomerang dysplasia."; RL J. Med. Genet. 42:E43-E43(2005). RN [40] RP VARIANTS [LARGE SCALE ANALYSIS] GLN-566; LYS-663; LYS-703 AND GLY-1534. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). RN [41] RP VARIANTS LRS CYS-161; SER-168; LYS-227; VAL-234; SER-361; GLU-363; RP ARG-1431; ASN-1571 DEL; ARG-1586; ASP-1592; LEU-1603; SER-1691 AND RP ARG-1834. RX PubMed=16801345; DOI=10.1136/jmg.2006.043687; RA Bicknell L.S., Farrington-Rock C., Shafeghati Y., Rump P., Alanay Y., RA Alembik Y., Al-Madani N., Firth H., Karimi-Nejad M.H., Kim C.A., Leask K., RA Maisenbacher M., Moran E., Pappas J.G., Prontera P., de Ravel T., RA Fryns J.-P., Sweeney E., Fryer A., Unger S., Wilson L.C., Lachman R.S., RA Rimoin D.L., Cohn D.H., Krakow D., Robertson S.P.; RT "A molecular and clinical study of Larsen syndrome caused by mutations in RT FLNB."; RL J. Med. Genet. 44:89-98(2007). CC -!- FUNCTION: Connects cell membrane constituents to the actin CC cytoskeleton. May promote orthogonal branching of actin filaments and CC links actin filaments to membrane glycoproteins. Anchors various CC transmembrane proteins to the actin cytoskeleton. Interaction with FLNA CC may allow neuroblast migration from the ventricular zone into the CC cortical plate. Various interactions and localizations of isoforms CC affect myotube morphology and myogenesis. Isoform 6 accelerates muscle CC differentiation in vitro. CC -!- SUBUNIT: Homodimer. Interacts with MICALL2 (By similarity). Interacts CC with RFLNA and RFLNB (By similarity). Isoform 1 interacts with FBLP1, CC FLNA, FLNC, GP1BA, INPPL1, ITGB1A, PSEN1 and PSEN2. Isoform 3 interacts CC with ITGB1A, ITGB1D, ITGB3 and ITGB6. Interacts with MYOT and MYOZ1. CC Interacts with HBV capsid protein. Interacts with ASB2 isoform 1; the CC interaction targets FLNB for proteasomal degradation (By similarity). CC {ECO:0000250, ECO:0000250|UniProtKB:Q80X90, CC ECO:0000269|PubMed:10754391, ECO:0000269|PubMed:11739414, CC ECO:0000269|PubMed:11807098, ECO:0000269|PubMed:12393796, CC ECO:0000269|PubMed:12496242, ECO:0000269|PubMed:12525170, CC ECO:0000269|PubMed:16076904, ECO:0000269|PubMed:9437013, CC ECO:0000269|PubMed:9651345, ECO:0000269|PubMed:9694715}. CC -!- INTERACTION: CC O75369; P21333: FLNA; NbExp=5; IntAct=EBI-352089, EBI-350432; CC O75369; O75369: FLNB; NbExp=4; IntAct=EBI-352089, EBI-352089; CC O75369; P62993: GRB2; NbExp=2; IntAct=EBI-352089, EBI-401755; CC O75369; P05161: ISG15; NbExp=4; IntAct=EBI-352089, EBI-746466; CC O75369; Q13233: MAP3K1; NbExp=2; IntAct=EBI-352089, EBI-49776; CC O75369; Q9Y6R4: MAP3K4; NbExp=2; IntAct=EBI-352089, EBI-448104; CC O75369; P16333: NCK1; NbExp=3; IntAct=EBI-352089, EBI-389883; CC O75369; P49768: PSEN1; NbExp=2; IntAct=EBI-352089, EBI-297277; CC O75369; P49810: PSEN2; NbExp=2; IntAct=EBI-352089, EBI-2010251; CC O75369; P63000: RAC1; NbExp=2; IntAct=EBI-352089, EBI-413628; CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm, cell cortex. Cytoplasm, CC cytoskeleton. Cytoplasm, cytoskeleton, stress fiber. Cytoplasm, CC myofibril, sarcomere, Z line. Note=In differentiating myotubes, isoform CC 1, isoform 2 and isoform 3 are localized diffusely throughout the CC cytoplasm with regions of enrichment at the longitudinal actin stress CC fiber. In differentiated tubes, isoform 1 is also detected within the CC Z-lines. CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm, cytoskeleton, stress CC fiber. CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Cytoplasm, cytoskeleton, stress CC fiber. CC -!- SUBCELLULAR LOCATION: [Isoform 6]: Cytoplasm, cytoskeleton. CC Note=Polarized at the periphery of myotubes. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=9; CC Name=1; Synonyms=ABP-278; CC IsoId=O75369-1; Sequence=Displayed; CC Name=2; Synonyms=ABP-276; CC IsoId=O75369-2; Sequence=VSP_008773; CC Name=3; Synonyms=Var-1; CC IsoId=O75369-3; Sequence=VSP_008774; CC Name=7; CC IsoId=O75369-7; Sequence=VSP_024113, VSP_024114, VSP_024115; CC Name=4; Synonyms=Var-3; CC IsoId=O75369-4; Sequence=VSP_008775, VSP_008776; CC Name=5; Synonyms=Var-2; CC IsoId=O75369-5; Sequence=VSP_008777, VSP_008778; CC Name=6; Synonyms=Var-1-DeltaH1; CC IsoId=O75369-6; Sequence=VSP_008773, VSP_008774; CC Name=8; CC IsoId=O75369-8; Sequence=VSP_043446; CC Name=9; CC IsoId=O75369-9; Sequence=VSP_024115; CC -!- TISSUE SPECIFICITY: Ubiquitous. Isoform 1 and isoform 2 are expressed CC in placenta, bone marrow, brain, umbilical vein endothelial cells CC (HUVEC), retina and skeletal muscle. Isoform 1 is predominantly CC expressed in prostate, uterus, liver, thyroid, stomach, lymph node, CC small intestine, spleen, skeletal muscle, kidney, placenta, pancreas, CC heart, lung, platelets, endothelial cells, megakaryocytic and CC erythroleukemic cell lines. Isoform 2 is predominantly expressed in CC spinal cord, platelet and Daudi cells. Also expressed in thyroid CC adenoma, neurofibrillary tangles (NFT), senile plaques in the CC hippocampus and cerebral cortex in Alzheimer disease (AD). Isoform 3 CC and isoform 6 are expressed predominantly in lung, heart, skeletal CC muscle, testis, spleen, thymus and leukocytes. Isoform 4 and isoform 5 CC are expressed in heart. {ECO:0000269|PubMed:11807098, CC ECO:0000269|PubMed:8327473, ECO:0000269|PubMed:9651345, CC ECO:0000269|PubMed:9694715}. CC -!- DOMAIN: Comprised of a NH2-terminal actin-binding domain, 24 internally CC homologous repeats and two hinge regions. Repeat 24 and the second CC hinge domain are important for dimer formation. The first hinge region CC prevents binding to ITGA and ITGB subunits. CC -!- PTM: ISGylation prevents ability to interact with the upstream CC activators of the JNK cascade and inhibits IFNA-induced JNK signaling. CC {ECO:0000269|PubMed:19270716}. CC -!- PTM: Ubiquitination by a SCF-like complex containing ASB2 isoform 1 CC leads to proteasomal degradation which promotes muscle differentiation. CC {ECO:0000269|PubMed:19300455}. CC -!- DISEASE: Note=Interaction with FLNA may compensate for dysfunctional CC FLNA homodimer in the periventricular nodular heterotopia (PVNH) CC disorder. CC -!- DISEASE: Atelosteogenesis 1 (AO1) [MIM:108720]: A lethal CC chondrodysplasia characterized by distal hypoplasia of the humeri and CC femurs, hypoplasia of the mid-thoracic spine, occasionally complete CC lack of ossification of single hand bones, and the finding in cartilage CC of multiple degenerated chondrocytes which are encapsulated in fibrous CC tissue. {ECO:0000269|PubMed:14991055}. Note=The disease is caused by CC variants affecting the gene represented in this entry. CC -!- DISEASE: Atelosteogenesis 3 (AO3) [MIM:108721]: A short-limb lethal CC skeletal dysplasia with vertebral abnormalities, disharmonious skeletal CC maturation, poorly modeled long bones and joint dislocations. Recurrent CC respiratory insufficiency and/or infections usually result in early CC death. {ECO:0000269|PubMed:14991055}. Note=The disease is caused by CC variants affecting the gene represented in this entry. CC -!- DISEASE: Boomerang dysplasia (BOOMD) [MIM:112310]: A perinatal lethal CC osteochondrodysplasia characterized by absence or underossification of CC the limb bones and vertebrae. Patients manifest dwarfism with short, CC bowed, rigid limbs and characteristic facies. Boomerang dysplasia is CC distinguished from atelosteogenesis on the basis of a more severe CC defect in mineralization, with complete absence of ossification in some CC limb elements and vertebral segments. {ECO:0000269|PubMed:15994868}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- DISEASE: Larsen syndrome (LRS) [MIM:150250]: An osteochondrodysplasia CC characterized by large-joint dislocations and characteristic CC craniofacial abnormalities. The cardinal features of the condition are CC dislocations of the hip, knee and elbow joints, with equinovarus or CC equinovalgus foot deformities. Spatula-shaped fingers, most marked in CC the thumb, are also present. Craniofacial anomalies include CC hypertelorism, prominence of the forehead, a depressed nasal bridge, CC and a flattened midface. Cleft palate and short stature are often CC associated features. Spinal anomalies include scoliosis and cervical CC kyphosis. Hearing loss is a well-recognized complication. CC {ECO:0000269|PubMed:14991055, ECO:0000269|PubMed:16801345}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Spondylocarpotarsal synostosis syndrome (SCT) [MIM:272460]: CC Disorder characterized by short stature and vertebral, carpal and CC tarsal fusions. {ECO:0000269|PubMed:14991055}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 2]: May be due to exon skipping. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 3]: May be due to exon skipping. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 5]: May be due to competing donor splice sites. CC {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 6]: May be due to exon skipping. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the filamin family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAA35505.1; Type=Frameshift; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF042166; AAC39842.1; -; mRNA. DR EMBL; AF043045; AAC33845.1; -; mRNA. DR EMBL; AF353666; AAL68439.1; -; mRNA. DR EMBL; AF353667; AAL68440.1; -; Genomic_DNA. DR EMBL; AF353667; AAL68441.1; -; Genomic_DNA. DR EMBL; AF353667; AAL68442.1; -; Genomic_DNA. DR EMBL; AF353667; AAL68443.1; -; Genomic_DNA. DR EMBL; AF191633; AAF72339.1; -; Genomic_DNA. DR EMBL; AF191594; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191595; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191596; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191597; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191598; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191599; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191600; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191601; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191602; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191603; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191604; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191605; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191606; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191607; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191608; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191609; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191611; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191610; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191613; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191612; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191614; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191615; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191617; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191616; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191618; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191619; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191620; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191621; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191622; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191623; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191624; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191625; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191627; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191626; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191628; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191629; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191630; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191631; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF191632; AAF72339.1; JOINED; Genomic_DNA. DR EMBL; AF238609; AAF97046.1; -; mRNA. DR EMBL; AB371580; BAG48309.1; -; mRNA. DR EMBL; AB371581; BAG48310.1; -; mRNA. DR EMBL; AB371582; BAG48311.1; -; mRNA. DR EMBL; AB191258; BAD52434.1; -; mRNA. DR EMBL; BX641085; CAE46040.1; -; mRNA. DR EMBL; AC114399; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC137936; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL137574; CAB70818.1; -; mRNA. DR EMBL; AB209889; BAD93126.1; -; mRNA. DR EMBL; M62994; AAA35505.1; ALT_FRAME; mRNA. DR CCDS; CCDS2885.1; -. [O75369-1] DR CCDS; CCDS54599.1; -. [O75369-8] DR CCDS; CCDS54600.1; -. [O75369-9] DR CCDS; CCDS54601.1; -. [O75369-2] DR PIR; T46270; T46270. DR RefSeq; NP_001157789.1; NM_001164317.2. [O75369-8] DR RefSeq; NP_001157790.1; NM_001164318.2. [O75369-9] DR RefSeq; NP_001157791.1; NM_001164319.2. [O75369-2] DR RefSeq; NP_001448.2; NM_001457.4. [O75369-1] DR PDB; 2DI8; NMR; -; A=1999-2096. DR PDB; 2DI9; NMR; -; A=1017-1134. DR PDB; 2DIA; NMR; -; A=1130-1229. DR PDB; 2DIB; NMR; -; A=1215-1329. DR PDB; 2DIC; NMR; -; A=1325-1422. DR PDB; 2DJ4; NMR; -; A=1418-1518. DR PDB; 2DLG; NMR; -; A=2104-2192. DR PDB; 2DMB; NMR; -; A=1611-1721. DR PDB; 2DMC; NMR; -; A=1899-2001. DR PDB; 2E9I; NMR; -; A=2094-2192. DR PDB; 2E9J; NMR; -; A=1504-1615. DR PDB; 2EE6; NMR; -; A=2190-2287. DR PDB; 2EE9; NMR; -; A=1736-1823. DR PDB; 2EEA; NMR; -; A=1808-1915. DR PDB; 2EEB; NMR; -; A=2284-2382. DR PDB; 2EEC; NMR; -; A=2371-2488. DR PDB; 2EED; NMR; -; A=2509-2602. DR PDB; 2WA5; X-ray; 1.90 A; A=2-242. DR PDB; 2WA6; X-ray; 1.95 A; A=2-242. DR PDB; 2WA7; X-ray; 1.85 A; A=2-242. DR PDB; 3FER; X-ray; 2.40 A; A/B/C/D=1-252. DR PDB; 4B7L; X-ray; 2.05 A; A/B=1-347. DR PDB; 5DCP; X-ray; 2.49 A; A/B=1737-1911. DR PDBsum; 2DI8; -. DR PDBsum; 2DI9; -. DR PDBsum; 2DIA; -. DR PDBsum; 2DIB; -. DR PDBsum; 2DIC; -. DR PDBsum; 2DJ4; -. DR PDBsum; 2DLG; -. DR PDBsum; 2DMB; -. DR PDBsum; 2DMC; -. DR PDBsum; 2E9I; -. DR PDBsum; 2E9J; -. DR PDBsum; 2EE6; -. DR PDBsum; 2EE9; -. DR PDBsum; 2EEA; -. DR PDBsum; 2EEB; -. DR PDBsum; 2EEC; -. DR PDBsum; 2EED; -. DR PDBsum; 2WA5; -. DR PDBsum; 2WA6; -. DR PDBsum; 2WA7; -. DR PDBsum; 3FER; -. DR PDBsum; 4B7L; -. DR PDBsum; 5DCP; -. DR AlphaFoldDB; O75369; -. DR SMR; O75369; -. DR BioGRID; 108606; 329. DR FunCoup; O75369; 1629. DR IntAct; O75369; 107. DR MINT; O75369; -. DR STRING; 9606.ENSP00000420213; -. DR ChEMBL; CHEMBL4295677; -. DR TCDB; 8.A.66.1.5; the dystrophin (dystrophin) family. DR CarbonylDB; O75369; -. DR GlyConnect; 2041; 2 N-Linked glycans (1 site). DR GlyCosmos; O75369; 5 sites, 5 glycans. DR GlyGen; O75369; 13 sites, 9 N-linked glycans (4 sites), 1 O-linked glycan (8 sites). DR iPTMnet; O75369; -. DR MetOSite; O75369; -. DR PhosphoSitePlus; O75369; -. DR SwissPalm; O75369; -. DR BioMuta; FLNB; -. DR CPTAC; CPTAC-511; -. DR jPOST; O75369; -. DR MassIVE; O75369; -. DR PaxDb; 9606-ENSP00000420213; -. DR PeptideAtlas; O75369; -. DR ProteomicsDB; 49938; -. [O75369-1] DR ProteomicsDB; 49939; -. [O75369-2] DR ProteomicsDB; 49940; -. [O75369-3] DR ProteomicsDB; 49941; -. [O75369-4] DR ProteomicsDB; 49942; -. [O75369-5] DR ProteomicsDB; 49943; -. [O75369-6] DR ProteomicsDB; 49944; -. [O75369-7] DR ProteomicsDB; 49945; -. [O75369-8] DR ProteomicsDB; 49946; -. [O75369-9] DR ProteomicsDB; 75100; -. DR Pumba; O75369; -. DR ABCD; O75369; 2 sequenced antibodies. DR Antibodypedia; 1496; 307 antibodies from 35 providers. DR DNASU; 2317; -. DR Ensembl; ENST00000295956.9; ENSP00000295956.5; ENSG00000136068.17. [O75369-1] DR Ensembl; ENST00000358537.7; ENSP00000351339.3; ENSG00000136068.17. [O75369-2] DR Ensembl; ENST00000429972.6; ENSP00000415599.2; ENSG00000136068.17. [O75369-9] DR Ensembl; ENST00000490882.5; ENSP00000420213.1; ENSG00000136068.17. [O75369-8] DR GeneID; 2317; -. DR KEGG; hsa:2317; -. DR MANE-Select; ENST00000295956.9; ENSP00000295956.5; NM_001457.4; NP_001448.2. DR UCSC; uc003djj.3; human. [O75369-1] DR AGR; HGNC:3755; -. DR ClinPGx; PA28173; -. DR CTD; 2317; -. DR DisGeNET; 2317; -. DR GeneCards; FLNB; -. DR GeneReviews; FLNB; -. DR HGNC; HGNC:3755; FLNB. DR HPA; ENSG00000136068; Low tissue specificity. DR MalaCards; FLNB; -. DR MIM; 108720; phenotype. DR MIM; 108721; phenotype. DR MIM; 112310; phenotype. DR MIM; 150250; phenotype. DR MIM; 272460; phenotype. DR MIM; 603381; gene. DR OpenTargets; ENSG00000136068; -. DR Orphanet; 1190; Atelosteogenesis type I. DR Orphanet; 56305; Atelosteogenesis type III. DR Orphanet; 1263; Boomerang dysplasia. DR Orphanet; 503; Larsen syndrome. DR Orphanet; 3275; Spondylocarpotarsal synostosis. DR VEuPathDB; HostDB:ENSG00000136068; -. DR eggNOG; KOG0518; Eukaryota. DR GeneTree; ENSGT00940000156286; -. DR HOGENOM; CLU_000783_0_0_1; -. DR InParanoid; O75369; -. DR OMA; RAVPCKV; -. DR OrthoDB; 5334309at2759; -. DR PAN-GO; O75369; 0 GO annotations based on evolutionary models. DR PhylomeDB; O75369; -. DR PathwayCommons; O75369; -. DR Reactome; R-HSA-1169408; ISG15 antiviral mechanism. DR SignaLink; O75369; -. DR SIGNOR; O75369; -. DR Agora; ENSG00000136068; -. DR BioGRID-ORCS; 2317; 14 hits in 1153 CRISPR screens. DR CD-CODE; DEE660B4; Stress granule. DR ChiTaRS; FLNB; human. DR EvolutionaryTrace; O75369; -. DR GeneWiki; FLNB; -. DR GenomeRNAi; 2317; -. DR Pharos; O75369; Tbio. DR PRO; PR:O75369; -. DR Proteomes; UP000005640; Chromosome 3. DR RNAct; O75369; protein. DR Bgee; ENSG00000136068; Expressed in mucosa of transverse colon and 201 other cell types or tissues. DR ExpressionAtlas; O75369; baseline and differential. DR GO; GO:0015629; C:actin cytoskeleton; TAS:ProtInc. DR GO; GO:0005903; C:brush border; IEA:Ensembl. DR GO; GO:0005938; C:cell cortex; IEA:UniProtKB-SubCell. DR GO; GO:0005737; C:cytoplasm; HDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005925; C:focal adhesion; HDA:UniProtKB. DR GO; GO:0016020; C:membrane; NAS:UniProtKB. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0045335; C:phagocytic vesicle; IEA:Ensembl. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0001725; C:stress fiber; IEA:UniProtKB-SubCell. DR GO; GO:0030018; C:Z disc; IEA:UniProtKB-SubCell. DR GO; GO:0003779; F:actin binding; NAS:UniProtKB. DR GO; GO:0051015; F:actin filament binding; IEA:InterPro. DR GO; GO:0045296; F:cadherin binding; HDA:BHF-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0030036; P:actin cytoskeleton organization; TAS:ProtInc. DR GO; GO:0071346; P:cellular response to type II interferon; IEA:Ensembl. DR GO; GO:0003382; P:epithelial cell morphogenesis; IEA:Ensembl. DR GO; GO:0003334; P:keratinocyte development; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR GO; GO:0007519; P:skeletal muscle tissue development; IEA:Ensembl. DR CDD; cd21309; CH_FLNB_rpt1; 1. DR CDD; cd21313; CH_FLNB_rpt2; 1. DR FunFam; 1.10.418.10:FF:000006; Filamin-B isoform A; 1. DR FunFam; 2.60.40.10:FF:000042; Filamin-B isoform B; 2. DR FunFam; 2.60.40.10:FF:000092; Filamin-B isoform B; 1. DR FunFam; 1.10.418.10:FF:000008; Filamin-B isoform C; 1. DR FunFam; 2.60.40.10:FF:000007; Filamin-B isoform C; 3. DR FunFam; 2.60.40.10:FF:000079; Filamin-B isoform C; 1. DR FunFam; 2.60.40.10:FF:000125; filamin-B isoform X1; 1. DR FunFam; 2.60.40.10:FF:000138; filamin-B isoform X1; 1. DR FunFam; 2.60.40.10:FF:000154; filamin-B isoform X1; 1. DR FunFam; 2.60.40.10:FF:000102; filamin-B isoform X2; 1. DR FunFam; 2.60.40.10:FF:000001; Filamin-C isoform b; 5. DR FunFam; 2.60.40.10:FF:000105; filamin-C isoform X1; 1. DR FunFam; 2.60.40.10:FF:000115; filamin-C isoform X1; 1. DR FunFam; 2.60.40.10:FF:000126; filamin-C isoform X1; 1. DR FunFam; 2.60.40.10:FF:000157; filamin-C isoform X1; 1. DR FunFam; 2.60.40.10:FF:000096; filamin-C isoform X2; 1. DR FunFam; 2.60.40.10:FF:000118; filamin-C isoform X2; 1. DR FunFam; 2.60.40.10:FF:000122; filamin-C isoform X2; 1. DR FunFam; 2.60.40.10:FF:000168; filamin-C isoform X2; 1. DR Gene3D; 1.10.418.10; Calponin-like domain; 2. DR Gene3D; 2.60.40.10; Immunoglobulins; 24. DR InterPro; IPR001589; Actinin_actin-bd_CS. DR InterPro; IPR001715; CH_dom. DR InterPro; IPR036872; CH_dom_sf. DR InterPro; IPR044801; Filamin. DR InterPro; IPR017868; Filamin/ABP280_repeat-like. DR InterPro; IPR001298; Filamin/ABP280_rpt. DR InterPro; IPR013783; Ig-like_fold. DR InterPro; IPR014756; Ig_E-set. DR PANTHER; PTHR38537:SF7; FILAMIN-B; 1. DR PANTHER; PTHR38537; JITTERBUG, ISOFORM N; 1. DR Pfam; PF00307; CH; 2. DR Pfam; PF00630; Filamin; 24. DR SMART; SM00033; CH; 2. DR SMART; SM00557; IG_FLMN; 24. DR SUPFAM; SSF47576; Calponin-homology domain, CH-domain; 1. DR SUPFAM; SSF81296; E set domains; 24. DR PROSITE; PS00019; ACTININ_1; 1. DR PROSITE; PS00020; ACTININ_2; 1. DR PROSITE; PS50021; CH; 2. DR PROSITE; PS50194; FILAMIN_REPEAT; 24. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Actin-binding; Alternative splicing; Cytoplasm; KW Cytoskeleton; Developmental protein; Differentiation; Disease variant; KW Dwarfism; Isopeptide bond; Myogenesis; Phosphoprotein; KW Proteomics identification; Reference proteome; Repeat; Ubl conjugation. FT CHAIN 1..2602 FT /note="Filamin-B" FT /id="PRO_0000087298" FT DOMAIN 16..122 FT /note="Calponin-homology (CH) 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00044" FT DOMAIN 139..242 FT /note="Calponin-homology (CH) 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00044" FT REPEAT 249..347 FT /note="Filamin 1" FT REPEAT 349..446 FT /note="Filamin 2" FT REPEAT 447..543 FT /note="Filamin 3" FT REPEAT 544..636 FT /note="Filamin 4" FT REPEAT 640..736 FT /note="Filamin 5" FT REPEAT 737..839 FT /note="Filamin 6" FT REPEAT 840..938 FT /note="Filamin 7" FT REPEAT 939..1034 FT /note="Filamin 8" FT REPEAT 1035..1127 FT /note="Filamin 9" FT REPEAT 1128..1222 FT /note="Filamin 10" FT REPEAT 1223..1322 FT /note="Filamin 11" FT REPEAT 1323..1415 FT /note="Filamin 12" FT REPEAT 1416..1511 FT /note="Filamin 13" FT REPEAT 1512..1608 FT /note="Filamin 14" FT REPEAT 1609..1704 FT /note="Filamin 15" FT REPEAT 1729..1813 FT /note="Filamin 16" FT REPEAT 1816..1908 FT /note="Filamin 17" FT REPEAT 1919..1994 FT /note="Filamin 18" FT REPEAT 1997..2089 FT /note="Filamin 19" FT REPEAT 2091..2185 FT /note="Filamin 20" FT REPEAT 2188..2280 FT /note="Filamin 21" FT REPEAT 2282..2375 FT /note="Filamin 22" FT REPEAT 2379..2471 FT /note="Filamin 23" FT REPEAT 2507..2601 FT /note="Filamin 24" FT REGION 1..239 FT /note="Actin-binding" FT REGION 244..267 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1128..1511 FT /note="Interaction with FBLP1" FT /evidence="ECO:0000269|PubMed:12496242" FT REGION 1705..1728 FT /note="Hinge 1" FT /evidence="ECO:0000250" FT REGION 1862..2148 FT /note="Interaction with the cytoplasmic tail of GP1BA" FT REGION 2060..2225 FT /note="Interaction with FLNA 1" FT REGION 2130..2602 FT /note="Interaction with INPPL1" FT /evidence="ECO:0000269|PubMed:11739414" FT REGION 2472..2602 FT /note="Self-association site, tail" FT /evidence="ECO:0000250" FT REGION 2472..2506 FT /note="Hinge 2" FT /evidence="ECO:0000250" FT REGION 2507..2602 FT /note="Interaction with FLNA 2" FT MOD_RES 216 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 519 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231" FT MOD_RES 681 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 730 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 886 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 932 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 983 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:16964243, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:19690332, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT MOD_RES 1028 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 1307 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 1316 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:24275569" FT MOD_RES 1433 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1505 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1602 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 1780 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q80X90" FT MOD_RES 2083 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 2107 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569" FT MOD_RES 2113 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 2369 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 2465 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:23186163" FT MOD_RES 2478 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:23186163" FT MOD_RES 2481 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 2492 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 2518 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:Q80X90" FT MOD_RES 2524 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:Q80X90" FT MOD_RES 2576 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT CROSSLNK 2468 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ISG15)" FT /evidence="ECO:0000269|PubMed:19270716" FT VAR_SEQ 1..169 FT /note="Missing (in isoform 7)" FT /evidence="ECO:0000303|PubMed:17974005" FT /id="VSP_024113" FT VAR_SEQ 170..181 FT /note="ALGALVDSCAPG -> MQEHSTRRRSLS (in isoform 7)" FT /evidence="ECO:0000303|PubMed:17974005" FT /id="VSP_024114" FT VAR_SEQ 1463 FT /note="R -> RADDTDSQSWRSPLKALSEFFKGDPKGDFNKT (in isoform FT 8)" FT /evidence="ECO:0000303|PubMed:16106752, FT ECO:0000303|PubMed:18487259" FT /id="VSP_043446" FT VAR_SEQ 1704..1727 FT /note="Missing (in isoform 2 and isoform 6)" FT /evidence="ECO:0000303|PubMed:16106752, FT ECO:0000303|PubMed:18487259, ECO:0000303|PubMed:9694715" FT /id="VSP_008773" FT VAR_SEQ 1717..1727 FT /note="Missing (in isoform 7 and isoform 9)" FT /evidence="ECO:0000303|PubMed:16106752, FT ECO:0000303|PubMed:17974005, ECO:0000303|PubMed:18487259" FT /id="VSP_024115" FT VAR_SEQ 2081..2121 FT /note="Missing (in isoform 3 and isoform 6)" FT /evidence="ECO:0000305" FT /id="VSP_008774" FT VAR_SEQ 2123..2150 FT /note="EINSSDMSAHVTSPSGRVTEAEIVPMGK -> GVRVMNCSAQILWGWRVQFH FT TGSRNQQQ (in isoform 4)" FT /evidence="ECO:0000305" FT /id="VSP_008775" FT VAR_SEQ 2123..2146 FT /note="EINSSDMSAHVTSPSGRVTEAEIV -> GVRVMNCSAQILWGWRVQFHTGSR FT (in isoform 5)" FT /evidence="ECO:0000305" FT /id="VSP_008777" FT VAR_SEQ 2147..2602 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000305" FT /id="VSP_008778" FT VAR_SEQ 2151..2602 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000305" FT /id="VSP_008776" FT VARIANT 161 FT /note="F -> C (in LRS; dbSNP:rs80356506)" FT /evidence="ECO:0000269|PubMed:14991055, FT ECO:0000269|PubMed:16801345" FT /id="VAR_033069" FT VARIANT 168 FT /note="G -> S (in LRS; dbSNP:rs80356504)" FT /evidence="ECO:0000269|PubMed:16801345" FT /id="VAR_033070" FT VARIANT 171 FT /note="L -> R (in BOOMD; dbSNP:rs80356494)" FT /evidence="ECO:0000269|PubMed:15994868" FT /id="VAR_033071" FT VARIANT 173 FT /note="A -> V (in AO1; dbSNP:rs121908894)" FT /evidence="ECO:0000269|PubMed:14991055" FT /id="VAR_033072" FT VARIANT 188 FT /note="S -> P (in AO1)" FT /evidence="ECO:0000269|PubMed:14991055" FT /id="VAR_033073" FT VARIANT 202 FT /note="M -> V (in AO1 and AO3; dbSNP:rs121908895)" FT /evidence="ECO:0000269|PubMed:14991055" FT /id="VAR_033074" FT VARIANT 227 FT /note="E -> K (in LRS; dbSNP:rs80356508)" FT /evidence="ECO:0000269|PubMed:14991055, FT ECO:0000269|PubMed:16801345" FT /id="VAR_033075" FT VARIANT 234 FT /note="L -> V (in LRS; dbSNP:rs80356507)" FT /evidence="ECO:0000269|PubMed:16801345" FT /id="VAR_033076" FT VARIANT 235 FT /note="S -> P (in BOOMD; dbSNP:rs121908896)" FT /evidence="ECO:0000269|PubMed:15994868" FT /id="VAR_033077" FT VARIANT 361 FT /note="G -> S (in LRS; dbSNP:rs80356509)" FT /evidence="ECO:0000269|PubMed:16801345" FT /id="VAR_033078" FT VARIANT 363 FT /note="G -> E (in LRS; dbSNP:rs80356510)" FT /evidence="ECO:0000269|PubMed:16801345" FT /id="VAR_033079" FT VARIANT 566 FT /note="R -> Q (in a breast cancer sample; somatic mutation; FT dbSNP:rs150747960)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_035917" FT VARIANT 663 FT /note="N -> K (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_035918" FT VARIANT 703 FT /note="T -> K (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_035919" FT VARIANT 751 FT /note="G -> R (in AO3; dbSNP:rs28937587)" FT /evidence="ECO:0000269|PubMed:14991055" FT /id="VAR_033080" FT VARIANT 1018 FT /note="V -> M (in dbSNP:rs2276742)" FT /id="VAR_017182" FT VARIANT 1157 FT /note="D -> N (in dbSNP:rs1131356)" FT /evidence="ECO:0000269|PubMed:11153914, FT ECO:0000269|PubMed:18487259, ECO:0000269|PubMed:9651345" FT /id="VAR_017183" FT VARIANT 1179 FT /note="E -> K (in dbSNP:rs17058845)" FT /id="VAR_031392" FT VARIANT 1431 FT /note="L -> R (in LRS; dbSNP:rs80356511)" FT /evidence="ECO:0000269|PubMed:16801345" FT /id="VAR_033081" FT VARIANT 1471 FT /note="V -> M (in dbSNP:rs12632456)" FT /evidence="ECO:0000269|PubMed:11153914, FT ECO:0000269|PubMed:18487259, ECO:0000269|PubMed:9651345" FT /id="VAR_031393" FT VARIANT 1534 FT /note="A -> G (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_035920" FT VARIANT 1571 FT /note="Missing (in LRS; dbSNP:rs80356512)" FT /evidence="ECO:0000269|PubMed:14991055, FT ECO:0000269|PubMed:16801345" FT /id="VAR_033082" FT VARIANT 1586 FT /note="G -> R (in LRS; dbSNP:rs80356513)" FT /evidence="ECO:0000269|PubMed:14991055, FT ECO:0000269|PubMed:16801345" FT /id="VAR_033083" FT VARIANT 1592 FT /note="V -> D (in LRS; dbSNP:rs80356514)" FT /evidence="ECO:0000269|PubMed:16801345" FT /id="VAR_033084" FT VARIANT 1603 FT /note="P -> L (in LRS; dbSNP:rs80356515)" FT /evidence="ECO:0000269|PubMed:16801345" FT /id="VAR_033085" FT VARIANT 1691 FT /note="G -> S (in LRS; dbSNP:rs80356503)" FT /evidence="ECO:0000269|PubMed:14991055, FT ECO:0000269|PubMed:16801345" FT /id="VAR_033086" FT VARIANT 1834 FT /note="G -> R (in LRS; dbSNP:rs80356516)" FT /evidence="ECO:0000269|PubMed:16801345" FT /id="VAR_033087" FT MUTAGEN 2468 FT /note="K->R: Cytoplasmic localization." FT /evidence="ECO:0000269|PubMed:19270716" FT CONFLICT 816 FT /note="A -> T (in Ref. 7; CAE46040)" FT /evidence="ECO:0000305" FT CONFLICT 924 FT /note="Y -> H (in Ref. 7; CAE46040)" FT /evidence="ECO:0000305" FT CONFLICT 1411 FT /note="F -> L (in Ref. 7; CAE46040)" FT /evidence="ECO:0000305" FT CONFLICT 1560 FT /note="E -> G (in Ref. 7; CAE46040)" FT /evidence="ECO:0000305" FT CONFLICT 1953 FT /note="L -> F (in Ref. 4; AAF97046)" FT /evidence="ECO:0000305" FT CONFLICT 2006 FT /note="K -> R (in Ref. 2; AAC33845)" FT /evidence="ECO:0000305" FT CONFLICT 2099 FT /note="I -> S (in Ref. 7; CAE46040)" FT /evidence="ECO:0000305" FT CONFLICT 2170 FT /note="K -> N (in Ref. 4; AAF97046)" FT /evidence="ECO:0000305" FT CONFLICT 2293 FT /note="M -> V (in Ref. 4; AAF97046 and 7; CAE46040)" FT /evidence="ECO:0000305" FT CONFLICT 2354 FT /note="V -> A (in Ref. 11; CAB70818)" FT /evidence="ECO:0000305" FT CONFLICT 2487 FT /note="S -> C (in Ref. 13; AAA35505)" FT /evidence="ECO:0000305" FT CONFLICT 2571 FT /note="V -> A (in Ref. 11; CAB70818)" FT /evidence="ECO:0000305" FT HELIX 5..10 FT /evidence="ECO:0007829|PDB:2WA5" FT HELIX 13..16 FT /evidence="ECO:0007829|PDB:2WA7" FT HELIX 17..30 FT /evidence="ECO:0007829|PDB:2WA7" FT HELIX 31..33 FT /evidence="ECO:0007829|PDB:2WA7" FT TURN 40..46 FT /evidence="ECO:0007829|PDB:2WA7" FT HELIX 48..58 FT /evidence="ECO:0007829|PDB:2WA7" FT HELIX 73..89 FT /evidence="ECO:0007829|PDB:2WA7" FT HELIX 99..103 FT /evidence="ECO:0007829|PDB:2WA7" FT HELIX 107..122 FT /evidence="ECO:0007829|PDB:2WA7" FT HELIX 141..152 FT /evidence="ECO:0007829|PDB:2WA7" FT HELIX 163..165 FT /evidence="ECO:0007829|PDB:2WA7" FT HELIX 169..178 FT /evidence="ECO:0007829|PDB:2WA7" FT HELIX 186..188 FT /evidence="ECO:0007829|PDB:2WA7" FT HELIX 194..208 FT /evidence="ECO:0007829|PDB:2WA7" FT HELIX 217..220 FT /evidence="ECO:0007829|PDB:2WA7" FT HELIX 227..234 FT /evidence="ECO:0007829|PDB:2WA7" FT HELIX 236..239 FT /evidence="ECO:0007829|PDB:2WA7" FT HELIX 254..256 FT /evidence="ECO:0007829|PDB:4B7L" FT STRAND 258..261 FT /evidence="ECO:0007829|PDB:4B7L" FT HELIX 262..264 FT /evidence="ECO:0007829|PDB:4B7L" FT STRAND 265..267 FT /evidence="ECO:0007829|PDB:4B7L" FT STRAND 275..280 FT /evidence="ECO:0007829|PDB:4B7L" FT TURN 282..284 FT /evidence="ECO:0007829|PDB:4B7L" FT STRAND 289..294 FT /evidence="ECO:0007829|PDB:4B7L" FT STRAND 300..302 FT /evidence="ECO:0007829|PDB:4B7L" FT STRAND 304..309 FT /evidence="ECO:0007829|PDB:4B7L" FT STRAND 313..319 FT /evidence="ECO:0007829|PDB:4B7L" FT STRAND 323..333 FT /evidence="ECO:0007829|PDB:4B7L" FT STRAND 342..347 FT /evidence="ECO:0007829|PDB:4B7L" FT HELIX 1040..1042 FT /evidence="ECO:0007829|PDB:2DI9" FT STRAND 1044..1047 FT /evidence="ECO:0007829|PDB:2DI9" FT HELIX 1048..1051 FT /evidence="ECO:0007829|PDB:2DI9" FT STRAND 1052..1054 FT /evidence="ECO:0007829|PDB:2DI9" FT STRAND 1059..1064 FT /evidence="ECO:0007829|PDB:2DI9" FT TURN 1066..1068 FT /evidence="ECO:0007829|PDB:2DI9" FT STRAND 1073..1077 FT /evidence="ECO:0007829|PDB:2DI9" FT STRAND 1079..1081 FT /evidence="ECO:0007829|PDB:2DI9" FT STRAND 1084..1089 FT /evidence="ECO:0007829|PDB:2DI9" FT STRAND 1091..1100 FT /evidence="ECO:0007829|PDB:2DI9" FT STRAND 1102..1115 FT /evidence="ECO:0007829|PDB:2DI9" FT STRAND 1122..1128 FT /evidence="ECO:0007829|PDB:2DI9" FT HELIX 1133..1135 FT /evidence="ECO:0007829|PDB:2DIA" FT STRAND 1136..1140 FT /evidence="ECO:0007829|PDB:2DIA" FT HELIX 1141..1143 FT /evidence="ECO:0007829|PDB:2DIA" FT STRAND 1154..1160 FT /evidence="ECO:0007829|PDB:2DIA" FT STRAND 1166..1172 FT /evidence="ECO:0007829|PDB:2DIA" FT TURN 1173..1175 FT /evidence="ECO:0007829|PDB:2DIA" FT STRAND 1179..1184 FT /evidence="ECO:0007829|PDB:2DIA" FT STRAND 1188..1195 FT /evidence="ECO:0007829|PDB:2DIA" FT STRAND 1200..1208 FT /evidence="ECO:0007829|PDB:2DIA" FT STRAND 1217..1223 FT /evidence="ECO:0007829|PDB:2DIA" FT STRAND 1232..1235 FT /evidence="ECO:0007829|PDB:2DIB" FT HELIX 1236..1239 FT /evidence="ECO:0007829|PDB:2DIB" FT STRAND 1249..1254 FT /evidence="ECO:0007829|PDB:2DIB" FT STRAND 1256..1258 FT /evidence="ECO:0007829|PDB:2DIB" FT STRAND 1273..1275 FT /evidence="ECO:0007829|PDB:2DIB" FT STRAND 1281..1284 FT /evidence="ECO:0007829|PDB:2DIB" FT STRAND 1286..1294 FT /evidence="ECO:0007829|PDB:2DIB" FT STRAND 1300..1310 FT /evidence="ECO:0007829|PDB:2DIB" FT STRAND 1317..1321 FT /evidence="ECO:0007829|PDB:2DIB" FT STRAND 1332..1335 FT /evidence="ECO:0007829|PDB:2DIC" FT HELIX 1336..1339 FT /evidence="ECO:0007829|PDB:2DIC" FT STRAND 1347..1352 FT /evidence="ECO:0007829|PDB:2DIC" FT TURN 1354..1356 FT /evidence="ECO:0007829|PDB:2DIC" FT STRAND 1361..1369 FT /evidence="ECO:0007829|PDB:2DIC" FT STRAND 1374..1377 FT /evidence="ECO:0007829|PDB:2DIC" FT STRAND 1379..1381 FT /evidence="ECO:0007829|PDB:2DIC" FT STRAND 1383..1387 FT /evidence="ECO:0007829|PDB:2DIC" FT STRAND 1393..1401 FT /evidence="ECO:0007829|PDB:2DIC" FT STRAND 1410..1416 FT /evidence="ECO:0007829|PDB:2DIC" FT STRAND 1425..1428 FT /evidence="ECO:0007829|PDB:2DJ4" FT TURN 1429..1431 FT /evidence="ECO:0007829|PDB:2DJ4" FT STRAND 1441..1446 FT /evidence="ECO:0007829|PDB:2DJ4" FT TURN 1448..1450 FT /evidence="ECO:0007829|PDB:2DJ4" FT STRAND 1455..1460 FT /evidence="ECO:0007829|PDB:2DJ4" FT STRAND 1462..1464 FT /evidence="ECO:0007829|PDB:2DJ4" FT STRAND 1475..1483 FT /evidence="ECO:0007829|PDB:2DJ4" FT STRAND 1489..1501 FT /evidence="ECO:0007829|PDB:2DJ4" FT STRAND 1506..1512 FT /evidence="ECO:0007829|PDB:2DJ4" FT HELIX 1517..1519 FT /evidence="ECO:0007829|PDB:2E9J" FT STRAND 1520..1524 FT /evidence="ECO:0007829|PDB:2E9J" FT HELIX 1525..1527 FT /evidence="ECO:0007829|PDB:2E9J" FT STRAND 1538..1546 FT /evidence="ECO:0007829|PDB:2E9J" FT STRAND 1566..1570 FT /evidence="ECO:0007829|PDB:2E9J" FT STRAND 1573..1580 FT /evidence="ECO:0007829|PDB:2E9J" FT STRAND 1586..1590 FT /evidence="ECO:0007829|PDB:2E9J" FT STRAND 1593..1596 FT /evidence="ECO:0007829|PDB:2E9J" FT STRAND 1603..1609 FT /evidence="ECO:0007829|PDB:2E9J" FT STRAND 1618..1621 FT /evidence="ECO:0007829|PDB:2DMB" FT HELIX 1622..1624 FT /evidence="ECO:0007829|PDB:2DMB" FT STRAND 1625..1639 FT /evidence="ECO:0007829|PDB:2DMB" FT STRAND 1641..1643 FT /evidence="ECO:0007829|PDB:2DMB" FT STRAND 1648..1653 FT /evidence="ECO:0007829|PDB:2DMB" FT STRAND 1663..1666 FT /evidence="ECO:0007829|PDB:2DMB" FT STRAND 1672..1677 FT /evidence="ECO:0007829|PDB:2DMB" FT STRAND 1682..1692 FT /evidence="ECO:0007829|PDB:2DMB" FT STRAND 1699..1705 FT /evidence="ECO:0007829|PDB:2DMB" FT STRAND 1747..1751 FT /evidence="ECO:0007829|PDB:5DCP" FT STRAND 1760..1765 FT /evidence="ECO:0007829|PDB:5DCP" FT STRAND 1775..1779 FT /evidence="ECO:0007829|PDB:5DCP" FT TURN 1780..1782 FT /evidence="ECO:0007829|PDB:5DCP" FT STRAND 1783..1788 FT /evidence="ECO:0007829|PDB:5DCP" FT STRAND 1794..1802 FT /evidence="ECO:0007829|PDB:5DCP" FT STRAND 1811..1816 FT /evidence="ECO:0007829|PDB:5DCP" FT STRAND 1825..1828 FT /evidence="ECO:0007829|PDB:5DCP" FT HELIX 1829..1831 FT /evidence="ECO:0007829|PDB:5DCP" FT STRAND 1833..1835 FT /evidence="ECO:0007829|PDB:5DCP" FT STRAND 1840..1845 FT /evidence="ECO:0007829|PDB:5DCP" FT STRAND 1855..1863 FT /evidence="ECO:0007829|PDB:5DCP" FT STRAND 1868..1870 FT /evidence="ECO:0007829|PDB:5DCP" FT STRAND 1872..1880 FT /evidence="ECO:0007829|PDB:5DCP" FT STRAND 1886..1898 FT /evidence="ECO:0007829|PDB:5DCP" FT STRAND 1903..1909 FT /evidence="ECO:0007829|PDB:5DCP" FT STRAND 1924..1927 FT /evidence="ECO:0007829|PDB:2DMC" FT STRAND 1941..1943 FT /evidence="ECO:0007829|PDB:2DMC" FT STRAND 1952..1957 FT /evidence="ECO:0007829|PDB:2DMC" FT TURN 1958..1960 FT /evidence="ECO:0007829|PDB:2DMC" FT STRAND 1961..1966 FT /evidence="ECO:0007829|PDB:2DMC" FT STRAND 1972..1977 FT /evidence="ECO:0007829|PDB:2DMC" FT STRAND 1979..1984 FT /evidence="ECO:0007829|PDB:2DMC" FT STRAND 1989..1994 FT /evidence="ECO:0007829|PDB:2DMC" FT STRAND 1997..1999 FT /evidence="ECO:0007829|PDB:2DMC" FT HELIX 2002..2004 FT /evidence="ECO:0007829|PDB:2DI8" FT STRAND 2006..2010 FT /evidence="ECO:0007829|PDB:2DI8" FT TURN 2011..2013 FT /evidence="ECO:0007829|PDB:2DI8" FT STRAND 2014..2016 FT /evidence="ECO:0007829|PDB:2DI8" FT STRAND 2021..2026 FT /evidence="ECO:0007829|PDB:2DI8" FT TURN 2028..2030 FT /evidence="ECO:0007829|PDB:2DI8" FT STRAND 2035..2043 FT /evidence="ECO:0007829|PDB:2DI8" FT STRAND 2057..2061 FT /evidence="ECO:0007829|PDB:2DI8" FT STRAND 2067..2077 FT /evidence="ECO:0007829|PDB:2DI8" FT STRAND 2084..2090 FT /evidence="ECO:0007829|PDB:2DI8" FT STRAND 2111..2113 FT /evidence="ECO:0007829|PDB:2DLG" FT STRAND 2118..2120 FT /evidence="ECO:0007829|PDB:2DLG" FT HELIX 2126..2128 FT /evidence="ECO:0007829|PDB:2DLG" FT STRAND 2130..2134 FT /evidence="ECO:0007829|PDB:2DLG" FT STRAND 2140..2142 FT /evidence="ECO:0007829|PDB:2DLG" FT STRAND 2144..2147 FT /evidence="ECO:0007829|PDB:2DLG" FT STRAND 2149..2157 FT /evidence="ECO:0007829|PDB:2DLG" FT STRAND 2164..2175 FT /evidence="ECO:0007829|PDB:2DLG" FT STRAND 2180..2185 FT /evidence="ECO:0007829|PDB:2DLG" FT HELIX 2193..2195 FT /evidence="ECO:0007829|PDB:2EE6" FT TURN 2201..2203 FT /evidence="ECO:0007829|PDB:2EE6" FT STRAND 2206..2208 FT /evidence="ECO:0007829|PDB:2EE6" FT STRAND 2210..2214 FT /evidence="ECO:0007829|PDB:2EE6" FT STRAND 2219..2221 FT /evidence="ECO:0007829|PDB:2EE6" FT STRAND 2226..2234 FT /evidence="ECO:0007829|PDB:2EE6" FT STRAND 2236..2240 FT /evidence="ECO:0007829|PDB:2EE6" FT STRAND 2250..2256 FT /evidence="ECO:0007829|PDB:2EE6" FT STRAND 2258..2266 FT /evidence="ECO:0007829|PDB:2EE6" FT STRAND 2275..2281 FT /evidence="ECO:0007829|PDB:2EE6" FT STRAND 2288..2294 FT /evidence="ECO:0007829|PDB:2EEB" FT STRAND 2306..2314 FT /evidence="ECO:0007829|PDB:2EEB" FT STRAND 2320..2324 FT /evidence="ECO:0007829|PDB:2EEB" FT STRAND 2330..2332 FT /evidence="ECO:0007829|PDB:2EEB" FT STRAND 2334..2337 FT /evidence="ECO:0007829|PDB:2EEB" FT STRAND 2340..2347 FT /evidence="ECO:0007829|PDB:2EEB" FT STRAND 2352..2365 FT /evidence="ECO:0007829|PDB:2EEB" FT STRAND 2370..2375 FT /evidence="ECO:0007829|PDB:2EEB" FT TURN 2384..2386 FT /evidence="ECO:0007829|PDB:2EEC" FT STRAND 2388..2392 FT /evidence="ECO:0007829|PDB:2EEC" FT TURN 2393..2395 FT /evidence="ECO:0007829|PDB:2EEC" FT STRAND 2403..2408 FT /evidence="ECO:0007829|PDB:2EEC" FT TURN 2410..2412 FT /evidence="ECO:0007829|PDB:2EEC" FT STRAND 2417..2425 FT /evidence="ECO:0007829|PDB:2EEC" FT STRAND 2430..2433 FT /evidence="ECO:0007829|PDB:2EEC" FT STRAND 2435..2442 FT /evidence="ECO:0007829|PDB:2EEC" FT STRAND 2448..2459 FT /evidence="ECO:0007829|PDB:2EEC" FT STRAND 2466..2473 FT /evidence="ECO:0007829|PDB:2EEC" FT TURN 2512..2514 FT /evidence="ECO:0007829|PDB:2EED" FT STRAND 2516..2519 FT /evidence="ECO:0007829|PDB:2EED" FT HELIX 2520..2523 FT /evidence="ECO:0007829|PDB:2EED" FT STRAND 2531..2536 FT /evidence="ECO:0007829|PDB:2EED" FT TURN 2538..2540 FT /evidence="ECO:0007829|PDB:2EED" FT STRAND 2545..2547 FT /evidence="ECO:0007829|PDB:2EED" FT STRAND 2557..2565 FT /evidence="ECO:0007829|PDB:2EED" FT STRAND 2568..2574 FT /evidence="ECO:0007829|PDB:2EED" FT STRAND 2579..2583 FT /evidence="ECO:0007829|PDB:2EED" FT STRAND 2585..2591 FT /evidence="ECO:0007829|PDB:2EED" FT STRAND 2596..2601 FT /evidence="ECO:0007829|PDB:2EED" FT MOD_RES O75369-8:1474 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" SQ SEQUENCE 2602 AA; 278164 MW; 1BF5C64C86360C6A CRC64; MPVTEKDLAE DAPWKKIQQN TFTRWCNEHL KCVNKRIGNL QTDLSDGLRL IALLEVLSQK RMYRKYHQRP TFRQMQLENV SVALEFLDRE SIKLVSIDSK AIVDGNLKLI LGLVWTLILH YSISMPVWED EGDDDAKKQT PKQRLLGWIQ NKIPYLPITN FNQNWQDGKA LGALVDSCAP GLCPDWESWD PQKPVDNARE AMQQADDWLG VPQVITPEEI IHPDVDEHSV MTYLSQFPKA KLKPGAPLKP KLNPKKARAY GRGIEPTGNM VKQPAKFTVD TISAGQGDVM VFVEDPEGNK EEAQVTPDSD KNKTYSVEYL PKVTGLHKVT VLFAGQHISK SPFEVSVDKA QGDASKVTAK GPGLEAVGNI ANKPTYFDIY TAGAGVGDIG VEVEDPQGKN TVELLVEDKG NQVYRCVYKP MQPGPHVVKI FFAGDTIPKS PFVVQVGEAC NPNACRASGR GLQPKGVRIR ETTDFKVDTK AAGSGELGVT MKGPKGLEEL VKQKDFLDGV YAFEYYPSTP GRYSIAITWG GHHIPKSPFE VQVGPEAGMQ KVRAWGPGLH GGIVGRSADF VVESIGSEVG SLGFAIEGPS QAKIEYNDQN DGSCDVKYWP KEPGEYAVHI MCDDEDIKDS PYMAFIHPAT GGYNPDLVRA YGPGLEKSGC IVNNLAEFTV DPKDAGKAPL KIFAQDGEGQ RIDIQMKNRM DGTYACSYTP VKAIKHTIAV VWGGVNIPHS PYRVNIGQGS HPQKVKVFGP GVERSGLKAN EPTHFTVDCT EAGEGDVSVG IKCDARVLSE DEEDVDFDII HNANDTFTVK YVPPAAGRYT IKVLFASQEI PASPFRVKVD PSHDASKVKA EGPGLSKAGV ENGKPTHFTV YTKGAGKAPL NVQFNSPLPG DAVKDLDIID NYDYSHTVKY TPTQQGNMQV LVTYGGDPIP KSPFTVGVAA PLDLSKIKLN GLENRVEVGK DQEFTVDTRG AGGQGKLDVT ILSPSRKVVP CLVTPVTGRE NSTAKFIPRE EGLYAVDVTY DGHPVPGSPY TVEASLPPDP SKVKAHGPGL EGGLVGKPAE FTIDTKGAGT GGLGLTVEGP CEAKIECSDN GDGTCSVSYL PTKPGEYFVN ILFEEVHIPG SPFKADIEMP FDPSKVVASG PGLEHGKVGE AGLLSVDCSE AGPGALGLEA VSDSGTKAEV SIQNNKDGTY AVTYVPLTAG MYTLTMKYGG ELVPHFPARV KVEPAVDTSR IKVFGPGIEG KDVFREATTD FTVDSRPLTQ VGGDHIKAHI ANPSGASTEC FVTDNADGTY QVEYTPFEKG LHVVEVTYDD VPIPNSPFKV AVTEGCQPSR VQAQGPGLKE AFTNKPNVFT VVTRGAGIGG LGITVEGPSE SKINCRDNKD GSCSAEYIPF APGDYDVNIT YGGAHIPGSP FRVPVKDVVD PSKVKIAGPG LGSGVRARVL QSFTVDSSKA GLAPLEVRVL GPRGLVEPVN VVDNGDGTHT VTYTPSQEGP YMVSVKYADE EIPRSPFKVK VLPTYDASKV TASGPGLSSY GVPASLPVDF AIDARDAGEG LLAVQITDQE GKPKRAIVHD NKDGTYAVTY IPDKTGRYMI GVTYGGDDIP LSPYRIRATQ TGDASKCLAT GPGIASTVKT GEEVGFVVDA KTAGKGKVTC TVLTPDGTEA EADVIENEDG TYDIFYTAAK PGTYVIYVRF GGVDIPNSPF TVMATDGEVT AVEEAPVNAC PPGFRPWVTE EAYVPVSDMN GLGFKPFDLV IPFAVRKGEI TGEVHMPSGK TATPEIVDNK DGTVTVRYAP TEVGLHEMHI KYMGSHIPES PLQFYVNYPN SGSVSAYGPG LVYGVANKTA TFTIVTEDAG EGGLDLAIEG PSKAEISCID NKDGTCTVTY LPTLPGDYSI LVKYNDKHIP GSPFTAKITD DSRRCSQVKL GSAADFLLDI SETDLSSLTA SIKAPSGRDE PCLLKRLPNN HIGISFIPRE VGEHLVSIKK NGNHVANSPV SIMVVQSEIG DARRAKVYGR GLSEGRTFEM SDFIVDTRDA GYGGISLAVE GPSKVDIQTE DLEDGTCKVS YFPTVPGVYI VSTKFADEHV PGSPFTVKIS GEGRVKESIT RTSRAPSVAT VGSICDLNLK IPEINSSDMS AHVTSPSGRV TEAEIVPMGK NSHCVRFVPQ EMGVHTVSVK YRGQHVTGSP FQFTVGPLGE GGAHKVRAGG PGLERGEAGV PAEFSIWTRE AGAGGLSIAV EGPSKAEITF DDHKNGSCGV SYIAQEPGNY EVSIKFNDEH IPESPYLVPV IAPSDDARRL TVMSLQESGL KVNQPASFAI RLNGAKGKID AKVHSPSGAV EECHVSELEP DKYAVRFIPH ENGVHTIDVK FNGSHVVGSP FKVRVGEPGQ AGNPALVSAY GTGLEGGTTG IQSEFFINTT RAGPGTLSVT IEGPSKVKMD CQETPEGYKV MYTPMAPGNY LISVKYGGPN HIVGSPFKAK VTGQRLVSPG SANETSSILV ESVTRSSTET CYSAIPKASS DASKVTSKGA GLSKAFVGQK SSFLVDCSKA GSNMLLIGVH GPTTPCEEVS MKHVGNQQYN VTYVVKERGD YVLAVKWGEE HIPGSPFHVT VP // ID FOLH1_HUMAN Reviewed; 750 AA. AC Q04609; A4UU12; A9CB79; B7Z312; B7Z343; D3DQS5; E9PDX8; O43748; Q16305; AC Q541A4; Q8TAY3; Q9NP15; Q9NYE2; Q9P1P8; DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-1994, sequence version 1. DT 28-JAN-2026, entry version 235. DE RecName: Full=Glutamate carboxypeptidase 2 {ECO:0000305}; DE EC=3.4.17.21; DE AltName: Full=Cell growth-inhibiting gene 27 protein; DE AltName: Full=Folate hydrolase 1; DE AltName: Full=Folylpoly-gamma-glutamate carboxypeptidase; DE Short=FGCP; DE AltName: Full=Glutamate carboxypeptidase II; DE Short=GCPII; DE AltName: Full=Membrane glutamate carboxypeptidase; DE Short=mGCP; DE AltName: Full=N-acetylated-alpha-linked acidic dipeptidase I; DE Short=NAALADase I; DE AltName: Full=Prostate-specific membrane antigen; DE Short=PSM; DE Short=PSMA; DE AltName: Full=Pteroylpoly-gamma-glutamate carboxypeptidase; GN Name=FOLH1 {ECO:0000312|HGNC:HGNC:3788}; Synonyms=FOLH, NAALAD1, PSM, PSMA; GN ORFNames=GIG27; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-1), AND PARTIAL PROTEIN SEQUENCE. RC TISSUE=Prostatic carcinoma; RX PubMed=8417812; RA Israeli R.S., Powell C.T., Fair W.R., Heston W.D.W.; RT "Molecular cloning of a complementary DNA encoding a prostate-specific RT membrane antigen."; RL Cancer Res. 53:227-230(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA'). RC TISSUE=Prostate; RX PubMed=7882349; RA Su S.L., Huang I.-P., Fair W.R., Powell C.T., Heston W.D.W.; RT "Alternatively spliced variants of prostate-specific membrane antigen RNA: RT ratio of expression as a potential measurement of progression."; RL Cancer Res. 55:1441-1443(1995). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM PSMA-1), AND VARIANT HIS-75. RX PubMed=9838072; DOI=10.1016/s0167-4781(98)00200-0; RA O'Keefe D.S., Su S.L., Bacich D.J., Horiguchi Y., Luo Y., Powell C.T., RA Zandvliet D., Russell P.J., Molloy P.L., Nowak N.J., Shows T.B., RA Mullins C., Vonder Haar R.A., Fair W.R., Heston W.D.W.; RT "Mapping, genomic organization and promoter analysis of the human prostate- RT specific membrane antigen gene."; RL Biochim. Biophys. Acta 1443:113-127(1998). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-1). RC TISSUE=Brain; RX PubMed=9694964; RA Luthi-Carter R., Barczak A.K., Speno H., Coyle J.T.; RT "Molecular characterization of human brain N-acetylated alpha-linked acidic RT dipeptidase (NAALADase)."; RL J. Pharmacol. Exp. Ther. 286:1020-1025(1998). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-1), AND CHARACTERIZATION. RC TISSUE=Prostate; RX PubMed=10085079; DOI=10.1074/jbc.274.13.8470; RA Pangalos M.N., Neefs J.-M., Somers M., Verhasselt P., Bekkers M., RA van der Helm L., Fraiponts E., Ashton D., Gordon R.D.; RT "Isolation and expression of novel human glutamate carboxypeptidases with RT N-acetylated alpha-linked acidic dipeptidase and dipeptidyl peptidase IV RT activity."; RL J. Biol. Chem. 274:8470-8483(1999). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-1), VARIANT TYR-475, AND TISSUE RP SPECIFICITY. RC TISSUE=Jejunum, and Small intestine; RX PubMed=11092759; DOI=10.1093/hmg/9.19.2837; RA Devlin A.M., Ling E.-H., Peerson J.M., Fernando S., Clarke R., Smith A.D., RA Halsted C.H.; RT "Glutamate carboxypeptidase II: a polymorphism associated with lower levels RT of serum folate and hyperhomocysteinemia."; RL Hum. Mol. Genet. 9:2837-2844(2000). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-1). RC TISSUE=Prostatic carcinoma; RA Ye C.Z., Zhang F.L., Zhang Y.K., Chen C.Q.; RT "Cloning and sequencing of Chinese prostate-specific membrane antigen."; RL Mian Yi Xue Za Zhi 17:328-330(2001). RN [8] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-9). RX PubMed=17929272; DOI=10.1002/pros.20664; RA Cao K.Y., Mao X.P., Wang D.H., Xu L., Yuan G.Q., Dai S.Q., Zheng B.J., RA Qiu S.P.; RT "High expression of PSM-E correlated with tumor grade in prostate cancer: a RT new alternatively spliced variant of prostate-specific membrane antigen."; RL Prostate 67:1791-1800(2007). RN [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Peace D.J., Zhang Y., Holt G., Ferrer K.T., Heller M., Sosman J.A., RA Xue B.H.; RT "Identification of three novel splice variants of prostate-specific RT membrane antigen."; RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-8). RA Kim J.W., Kim H.K., Shin S.M.; RT "Identification of a cell growth-inhibiting gene."; RL Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases. RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS PSMA-1; PSMA-7 AND 10). RC TISSUE=Amygdala, Corpus callosum, and Hippocampus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [12] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16554811; DOI=10.1038/nature04632; RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G., RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., RA Hattori M., Rogers J., Lander E.S., Sakaki Y.; RT "Human chromosome 11 DNA sequence and analysis including novel gene RT identification."; RL Nature 440:497-500(2006). RN [13] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [14] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM PSMA-8). RC TISSUE=Lung; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [15] RP PROTEIN SEQUENCE OF 60-74, AND SUBCELLULAR LOCATION. RC TISSUE=Prostatic carcinoma; RX PubMed=9809977; RA Grauer L.S., Lawler K.D., Marignac J.L., Kumar A., Goel A.S., Wolfert R.L.; RT "Identification, purification, and subcellular localization of prostate- RT specific membrane antigen PSM' protein in the LNCaP prostatic carcinoma RT cell line."; RL Cancer Res. 58:4787-4789(1998). RN [16] RP NUCLEOTIDE SEQUENCE [MRNA] OF 160-750 (ISOFORM PSMA-4), AND NUCLEOTIDE RP SEQUENCE [MRNA] OF 586-750 (ISOFORM PSMA-3). RA Lupold S.E., Criley S.C., Coffey D.S.; RT "Alternative splicing of the prostate-specific membrane antigen."; RL Submitted (APR-2000) to the EMBL/GenBank/DDBJ databases. RN [17] RP ALTERNATIVE SPLICING. RA Bzdega T., She D., Turi T., Wroblewska B., Neale J.H.; RT "Molecular cloning of alternatively spliced variants of the peptidase RT against N-acetylaspartylglutamate (NAAG) from human and rat nervous RT systems."; RL Abstr. - Soc. Neurosci. 24:579-579(1998). RN [18] RP CHARACTERIZATION. RX PubMed=9622670; DOI=10.1016/s0006-8993(98)00244-3; RA Luthi-Carter R., Barczak A.K., Speno H.D., Coyle J.T.; RT "Hydrolysis of the neuropeptide N-acetylaspartylglutamate (NAAG) by cloned RT human glutamate carboxypeptidase II."; RL Brain Res. 795:341-348(1998). RN [19] RP DOMAIN STRUCTURE. RX PubMed=9187245; DOI=10.1016/s0167-4838(97)00008-3; RA Rawlings N.D., Barrett A.J.; RT "Structure of membrane glutamate carboxypeptidase."; RL Biochim. Biophys. Acta 1339:247-252(1997). RN [20] RP MUTAGENESIS. RX PubMed=9882712; DOI=10.1124/mol.55.1.179; RA Speno H.S., Luthi-Carter R., Macias W.L., Valentine S.L., Joshi A.R.T., RA Coyle J.T.; RT "Site-directed mutagenesis of predicted active site residues in glutamate RT carboxypeptidase II."; RL Mol. Pharmacol. 55:179-185(1999). RN [21] RP GLYCOSYLATION AT ASN-76; ASN-336; ASN-459; ASN-476 AND ASN-638. RX PubMed=12754519; DOI=10.1038/nbt827; RA Zhang H., Li X.-J., Martin D.B., Aebersold R.; RT "Identification and quantification of N-linked glycoproteins using RT hydrazide chemistry, stable isotope labeling and mass spectrometry."; RL Nat. Biotechnol. 21:660-666(2003). RN [22] RP GLYCOSYLATION AT ASN-51; ASN-76; ASN-121; ASN-140; ASN-153; ASN-195; RP ASN-336; ASN-459; ASN-476 AND ASN-638, AND MUTAGENESIS OF ASN-51; ASN-76; RP ASN-121; ASN-140; ASN-153; ASN-195; ASN-336; ASN-459; ASN-476; ASN-638 AND RP THR-640. RX PubMed=15152093; DOI=10.1110/ps.04622104; RA Barinka C., Sacha P., Sklenar J., Man P., Bezouska K., Slusher B.S., RA Konvalinka J.; RT "Identification of the N-glycosylation sites on glutamate carboxypeptidase RT II necessary for proteolytic activity."; RL Protein Sci. 13:1627-1635(2004). RN [23] RP TISSUE SPECIFICITY. RC TISSUE=Liver; RX PubMed=14716746; DOI=10.1002/pros.10319; RA O'Keefe D.S., Bacich D.J., Heston W.D.W.; RT "Comparative analysis of prostate-specific membrane antigen (PSMA) versus a RT prostate-specific membrane antigen-like gene."; RL Prostate 58:200-210(2004). RN [24] RP TISSUE SPECIFICITY. RX PubMed=16555021; DOI=10.1007/s00268-005-0544-5; RA Kinoshita Y., Kuratsukuri K., Landas S., Imaida K., Rovito P.M. Jr., RA Wang C.Y., Haas G.P.; RT "Expression of prostate-specific membrane antigen in normal and malignant RT human tissues."; RL World J. Surg. 30:628-636(2006). RN [25] RP TISSUE SPECIFICITY. RX PubMed=17150306; DOI=10.1016/j.neuroscience.2006.10.022; RA Sacha P., Zamecnik J., Barinka C., Hlouchova K., Vicha A., Mlcochova P., RA Hilgert I., Eckschlager T., Konvalinka J.; RT "Expression of glutamate carboxypeptidase II in human brain."; RL Neuroscience 144:1361-1372(2007). RN [26] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 44-750 IN COMPLEXES WITH RP GLUTAMATE; INHIBITORS; CALCIUM AND ZINC IONS, COFACTOR, SUBUNIT, AND RP GLYCOSYLATION AT ASN-76; ASN-121; ASN-140; ASN-195; ASN-459; ASN-476 AND RP ASN-638. RX PubMed=16467855; DOI=10.1038/sj.emboj.7600969; RA Mesters J.R., Barinka C., Li W., Tsukamoto T., Majer P., Slusher B.S., RA Konvalinka J., Hilgenfeld R.; RT "Structure of glutamate carboxypeptidase II, a drug target in neuronal RT damage and prostate cancer."; RL EMBO J. 25:1375-1384(2006). RN [27] RP X-RAY CRYSTALLOGRAPHY (2.19 ANGSTROMS) OF 44-750 IN COMPLEXES WITH THE RP INHIBITORS QUISQUALATE AND 2-PMPA; CALCIUM AND ZINC IONS, AND GLYCOSYLATION RP AT ASN-76; ASN-121; ASN-140; ASN-195; ASN-459; ASN-476 AND ASN-638. RX PubMed=17372356; DOI=10.1107/s090744490700902x; RA Mesters J.R., Henning K., Hilgenfeld R.; RT "Human glutamate carboxypeptidase II inhibition: structures of GCPII in RT complex with two potent inhibitors, quisqualate and 2-PMPA."; RL Acta Crystallogr. D 63:508-513(2007). RN [28] RP X-RAY CRYSTALLOGRAPHY (1.62 ANGSTROMS) OF 44-750 IN COMPLEXES WITH RP SUBSTRATE ANALOGS; CALCIUM AND ZINC IONS, ACTIVITY REGULATION, AND RP GLYCOSYLATION AT ASN-76; ASN-121; ASN-140 ASN-195; ASN-459; ASN-476 AND RP ASN-638. RX PubMed=17567119; DOI=10.1021/jm070133w; RA Barinka C., Rovenska M., Mlcochova P., Hlouchova K., Plechanovova A., RA Majer P., Tsukamoto T., Slusher B.S., Konvalinka J., Lubkowski J.; RT "Structural insight into the pharmacophore pocket of human glutamate RT carboxypeptidase II."; RL J. Med. Chem. 50:3267-3273(2007). RN [29] RP X-RAY CRYSTALLOGRAPHY (1.54 ANGSTROMS) OF 44-750 IN COMPLEXES WITH RP UREA-BASED INHIBITORS; CALCIUM AND ZINC IONS, AND GLYCOSYLATION AT ASN-76; RP ASN-121; ASN-140; ASN-195; ASN-459; ASN-476 AND ASN-638. RX PubMed=19053759; DOI=10.1021/jm800765e; RA Barinka C., Byun Y., Dusich C.L., Banerjee S.R., Chen Y., Castanares M., RA Kozikowski A.P., Mease R.C., Pomper M.G., Lubkowski J.; RT "Interactions between human glutamate carboxypeptidase II and urea-based RT inhibitors: structural characterization."; RL J. Med. Chem. 51:7737-7743(2008). RN [30] RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 44-750 IN COMPLEXES WITH SUBSTRATE RP ANALOGS; CALCIUM AND ZINC IONS, AND GLYCOSYLATION AT ASN-76; ASN-121; RP ASN-140; ASN-195; ASN-459; ASN-476 AND ASN-638. RX PubMed=18234225; DOI=10.1016/j.jmb.2007.12.066; RA Barinka C., Hlouchova K., Rovenska M., Majer P., Dauter M., Hin N., RA Ko Y.-S., Tsukamoto T., Slusher B.S., Konvalinka J., Lubkowski J.; RT "Structural basis of interactions between human glutamate carboxypeptidase RT II and its substrate analogs."; RL J. Mol. Biol. 376:1438-1450(2008). RN [31] RP X-RAY CRYSTALLOGRAPHY (1.71 ANGSTROMS) OF 44-750 IN COMPLEX WITH SUBSTRATE; RP CALCIUM AND ZINC IONS, GLYCOSYLATION AT ASN-76; ASN-121; ASN-140; ASN-195; RP ASN-459; ASN-476 AND ASN-638, AND MUTAGENESIS OF GLU-424. RX PubMed=19301871; DOI=10.1021/bi900220s; RA Klusak V., Barinka C., Plechanovova A., Mlcochova P., Konvalinka J., RA Rulisek L., Lubkowski J.; RT "Reaction mechanism of glutamate carboxypeptidase II revealed by RT mutagenesis, X-ray crystallography, and computational methods."; RL Biochemistry 48:4126-4138(2009). RN [32] RP VARIANT [LARGE SCALE ANALYSIS] THR-23. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). CC -!- FUNCTION: Has both folate hydrolase and N-acetylated-alpha-linked- CC acidic dipeptidase (NAALADase) activity. Has a preference for tri- CC alpha-glutamate peptides. In the intestine, required for the uptake of CC folate. In the brain, modulates excitatory neurotransmission through CC the hydrolysis of the neuropeptide, N-aceylaspartylglutamate (NAAG), CC thereby releasing glutamate. Involved in prostate tumor progression. CC -!- FUNCTION: Also exhibits a dipeptidyl-peptidase IV type activity. In CC vitro, cleaves Gly-Pro-AMC. CC -!- CATALYTIC ACTIVITY: CC Reaction=Release of an unsubstituted, C-terminal glutamyl residue, CC typically from Ac-Asp-Glu or folylpoly-gamma-glutamates.; CC EC=3.4.17.21; CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Evidence={ECO:0000269|PubMed:16467855, ECO:0000269|PubMed:17372356, CC ECO:0000269|PubMed:17567119, ECO:0000269|PubMed:18234225, CC ECO:0000269|PubMed:19053759, ECO:0000269|PubMed:19301871}; CC Note=Binds 2 Zn(2+) ions per subunit. Required for NAALADase activity. CC {ECO:0000269|PubMed:16467855}; CC -!- ACTIVITY REGULATION: The NAALADase activity is inhibited by beta-NAAG, CC quisqualic acid, 2-(phosphonomethyl) pentanedioic acid (PMPA) and EDTA. CC Activated by cobalt. {ECO:0000269|PubMed:17567119}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC pH dependence: CC Stable at pH greater than 6.5.; CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:16467855, CC ECO:0000269|PubMed:19301871}. CC -!- INTERACTION: CC Q04609-8; Q5BVD1: TTMP; NbExp=3; IntAct=EBI-13060980, EBI-10243654; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:9809977}; CC Single-pass type II membrane protein {ECO:0000269|PubMed:9809977}. CC -!- SUBCELLULAR LOCATION: [Isoform PSMA']: Cytoplasm CC {ECO:0000269|PubMed:9809977}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=8; CC Name=PSMA-1; CC IsoId=Q04609-1; Sequence=Displayed; CC Name=PSMA-3; CC IsoId=Q04609-3; Sequence=VSP_040245; CC Name=PSMA-4; CC IsoId=Q04609-4; Sequence=VSP_040243, VSP_040244; CC Name=PSMA'; CC IsoId=Q04609-6; Sequence=VSP_005336; CC Name=PSMA-7; CC IsoId=Q04609-7; Sequence=VSP_038058; CC Name=PSMA-8; CC IsoId=Q04609-8; Sequence=VSP_038059; CC Name=PSMA-9; Synonyms=PSM-E; CC IsoId=Q04609-9; Sequence=VSP_038058, VSP_038059; CC Name=10; CC IsoId=Q04609-10; Sequence=VSP_044287; CC -!- TISSUE SPECIFICITY: Highly expressed in prostate epithelium. Detected CC in urinary bladder, kidney, testis, ovary, fallopian tube, breast, CC adrenal gland, liver, esophagus, stomach, small intestine, colon and CC brain (at protein level). Detected in the small intestine, brain, CC kidney, liver, spleen, colon, trachea, spinal cord and the capillary CC endothelium of a variety of tumors. Expressed specifically in jejunum CC brush border membranes. In the brain, highly expressed in the ventral CC striatum and brain stem. Also expressed in fetal liver and kidney. CC Isoform PSMA' is the most abundant form in normal prostate. Isoform CC PSMA-1 is the most abundant form in primary prostate tumors. Isoform CC PSMA-9 is specifically expressed in prostate cancer. CC {ECO:0000269|PubMed:11092759, ECO:0000269|PubMed:14716746, CC ECO:0000269|PubMed:16555021, ECO:0000269|PubMed:17150306}. CC -!- INDUCTION: In the prostate, up-regulated in response to androgen CC deprivation. CC -!- DOMAIN: The NAALADase activity is found in the central region, the CC dipeptidyl peptidase IV type activity in the C-terminal. CC {ECO:0000269|PubMed:9187245}. CC -!- PTM: The first two amino acids at the N-terminus of isoform PSMA' CC appear to be cleaved by limited proteolysis. CC -!- PTM: The N-terminus is blocked. CC -!- POLYMORPHISM: Genetic variation in FOLH1 may be associated with low CC folate levels and consequent hyperhomocysteinemia. This condition can CC result in increased risk of cardiovascular disease, neural tube CC defects, and cognitive deficits. CC -!- MISCELLANEOUS: PSMA is used as a diagnostic and prognostic indicator of CC prostate cancer, and as a possible marker for various neurological CC disorders such as schizophrenia, Alzheimer disease and Huntington CC disease. CC -!- SIMILARITY: Belongs to the peptidase M28 family. M28B subfamily. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAF31167.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M99487; AAA60209.1; -; mRNA. DR EMBL; S76978; AAB33750.2; -; mRNA. DR EMBL; AF007544; AAC83972.1; -; Genomic_DNA. DR EMBL; AF176574; AAD51121.1; -; mRNA. DR EMBL; EF488811; ABO93402.2; -; mRNA. DR EMBL; AY101595; AAM34479.1; -; mRNA. DR EMBL; AF107214; AAF31167.1; ALT_SEQ; Genomic_DNA. DR EMBL; DQ088979; AAZ66619.1; -; mRNA. DR EMBL; AK312366; BAG35284.1; -; mRNA. DR EMBL; AK295368; BAH12048.1; -; mRNA. DR EMBL; AK295470; BAH12079.1; -; mRNA. DR EMBL; AC110742; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC118273; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471064; EAW67858.1; -; Genomic_DNA. DR EMBL; CH471064; EAW67861.1; -; Genomic_DNA. DR EMBL; CH471064; EAW67857.1; -; Genomic_DNA. DR EMBL; CH471064; EAW67859.1; -; Genomic_DNA. DR EMBL; BC025672; AAH25672.1; -; mRNA. DR EMBL; AF254357; AAF71357.1; -; mRNA. DR EMBL; AF254358; AAF71358.1; -; mRNA. DR CCDS; CCDS31493.1; -. [Q04609-8] DR CCDS; CCDS53627.1; -. [Q04609-9] DR CCDS; CCDS53628.1; -. [Q04609-7] DR CCDS; CCDS7946.1; -. [Q04609-1] DR PIR; A56881; A56881. DR RefSeq; NP_001014986.1; NM_001014986.3. [Q04609-8] DR RefSeq; NP_001180400.1; NM_001193471.3. [Q04609-7] DR RefSeq; NP_001180401.1; NM_001193472.3. [Q04609-9] DR RefSeq; NP_001180402.1; NM_001193473.3. [Q04609-10] DR RefSeq; NP_004467.1; NM_004476.3. [Q04609-1] DR RefSeq; XP_016872923.1; XM_017017434.2. [Q04609-7] DR RefSeq; XP_047282634.1; XM_047426678.1. [Q04609-6] DR RefSeq; XP_047282635.1; XM_047426679.1. [Q04609-6] DR RefSeq; XP_047282636.1; XM_047426680.1. [Q04609-6] DR PDB; 1Z8L; X-ray; 3.50 A; A/B/C/D=56-750. DR PDB; 2C6C; X-ray; 2.00 A; A=44-750. DR PDB; 2C6G; X-ray; 2.20 A; A=44-750. DR PDB; 2C6P; X-ray; 2.39 A; A=44-750. DR PDB; 2CIJ; X-ray; 2.40 A; A=44-750. DR PDB; 2JBJ; X-ray; 2.19 A; A=44-750. DR PDB; 2JBK; X-ray; 2.99 A; A=44-750. DR PDB; 2OOT; X-ray; 1.64 A; A=44-750. DR PDB; 2OR4; X-ray; 1.62 A; A=44-750. DR PDB; 2PVV; X-ray; 2.11 A; A=44-750. DR PDB; 2PVW; X-ray; 1.71 A; A=44-750. DR PDB; 2XEF; X-ray; 1.59 A; A=44-750. DR PDB; 2XEG; X-ray; 1.59 A; A=44-750. DR PDB; 2XEI; X-ray; 1.69 A; A=44-750. DR PDB; 2XEJ; X-ray; 1.78 A; A=44-750. DR PDB; 3BHX; X-ray; 1.60 A; A=44-750. DR PDB; 3BI0; X-ray; 1.67 A; A=44-750. DR PDB; 3BI1; X-ray; 1.50 A; A=44-750. DR PDB; 3BXM; X-ray; 1.71 A; A=44-750. DR PDB; 3D7D; X-ray; 1.69 A; A=44-750. DR PDB; 3D7F; X-ray; 1.54 A; A=44-750. DR PDB; 3D7G; X-ray; 1.75 A; A=44-750. DR PDB; 3D7H; X-ray; 1.55 A; A=44-750. DR PDB; 3IWW; X-ray; 2.30 A; A=44-750. DR PDB; 3RBU; X-ray; 1.60 A; A=44-750. DR PDB; 3SJE; X-ray; 1.70 A; A=44-750. DR PDB; 3SJF; X-ray; 1.65 A; A=44-750. DR PDB; 3SJG; X-ray; 1.65 A; A=44-750. DR PDB; 3SJX; X-ray; 1.66 A; A=44-750. DR PDB; 4JYW; X-ray; 1.73 A; A=44-750. DR PDB; 4JZ0; X-ray; 1.83 A; A=44-750. DR PDB; 4LQG; X-ray; 1.77 A; A=44-750. DR PDB; 4MCP; X-ray; 1.65 A; A=44-750. DR PDB; 4MCQ; X-ray; 2.00 A; A=44-750. DR PDB; 4MCR; X-ray; 1.65 A; A=44-750. DR PDB; 4MCS; X-ray; 1.83 A; A=44-750. DR PDB; 4NGM; X-ray; 1.84 A; A=44-750. DR PDB; 4NGN; X-ray; 1.64 A; A=44-750. DR PDB; 4NGP; X-ray; 1.63 A; A=44-750. DR PDB; 4NGQ; X-ray; 2.08 A; A=44-750. DR PDB; 4NGR; X-ray; 1.90 A; A=44-750. DR PDB; 4NGS; X-ray; 1.68 A; A=44-750. DR PDB; 4NGT; X-ray; 2.31 A; A=44-750. DR PDB; 4OC0; X-ray; 1.85 A; A=44-750. DR PDB; 4OC1; X-ray; 1.75 A; A=44-750. DR PDB; 4OC2; X-ray; 1.65 A; A=44-750. DR PDB; 4OC3; X-ray; 1.79 A; A=44-750. DR PDB; 4OC4; X-ray; 1.66 A; A=44-750. DR PDB; 4OC5; X-ray; 1.70 A; A=44-750. DR PDB; 4OME; X-ray; 1.79 A; A=44-750. DR PDB; 4P44; X-ray; 1.75 A; A=44-750. DR PDB; 4P45; X-ray; 1.87 A; A=44-750. DR PDB; 4P4B; X-ray; 1.93 A; A=44-750. DR PDB; 4P4D; X-ray; 1.65 A; A=44-750. DR PDB; 4P4E; X-ray; 1.67 A; A=44-750. DR PDB; 4P4F; X-ray; 1.86 A; A=44-750. DR PDB; 4P4I; X-ray; 1.87 A; A=44-750. DR PDB; 4P4J; X-ray; 1.66 A; A=44-750. DR PDB; 4W9Y; X-ray; 1.64 A; A=44-750. DR PDB; 4X3R; X-ray; 1.86 A; A=44-750. DR PDB; 5D29; X-ray; 1.80 A; A=56-750. DR PDB; 5ELY; X-ray; 1.81 A; A=55-750. DR PDB; 5F09; X-ray; 1.85 A; A=44-750. DR PDB; 5O5R; X-ray; 1.65 A; A=44-750. DR PDB; 5O5T; X-ray; 1.43 A; A=44-750. DR PDB; 5O5U; X-ray; 1.53 A; A=44-750. DR PDB; 5OF0; X-ray; 1.48 A; A=44-750. DR PDB; 6ETY; X-ray; 1.68 A; A=44-750. DR PDB; 6EZ9; X-ray; 1.61 A; A=44-750. DR PDB; 6F5L; X-ray; 1.63 A; A=44-750. DR PDB; 6FE5; X-ray; 1.52 A; A=44-750. DR PDB; 6H7Y; X-ray; 1.81 A; A=44-750. DR PDB; 6H7Z; X-ray; 2.00 A; A=44-750. DR PDB; 6HKJ; X-ray; 2.09 A; A=44-750. DR PDB; 6HKZ; X-ray; 2.09 A; A=44-750. DR PDB; 6RBC; X-ray; 1.77 A; A=44-750. DR PDB; 6RTI; X-ray; 2.20 A; A=44-750. DR PDB; 6S1X; X-ray; 1.76 A; A=44-750. DR PDB; 6SGP; X-ray; 1.58 A; A=44-750. DR PDB; 6SKH; X-ray; 1.58 A; A=44-750. DR PDB; 7BFZ; X-ray; 1.73 A; A=44-750. DR PDB; 8BO8; X-ray; 1.55 A; A=44-750. DR PDB; 8BOL; X-ray; 1.55 A; A=44-750. DR PDB; 8BOW; X-ray; 1.58 A; A=44-750. DR PDB; 9HLW; EM; 2.66 A; A/E=1-750. DR PDB; 9HVI; EM; 2.46 A; A/E=56-750. DR PDB; 9HVK; EM; 3.00 A; A/E=56-750. DR PDB; 9HVL; EM; 2.71 A; A/E=56-750. DR PDBsum; 1Z8L; -. DR PDBsum; 2C6C; -. DR PDBsum; 2C6G; -. DR PDBsum; 2C6P; -. DR PDBsum; 2CIJ; -. DR PDBsum; 2JBJ; -. DR PDBsum; 2JBK; -. DR PDBsum; 2OOT; -. DR PDBsum; 2OR4; -. DR PDBsum; 2PVV; -. DR PDBsum; 2PVW; -. DR PDBsum; 2XEF; -. DR PDBsum; 2XEG; -. DR PDBsum; 2XEI; -. DR PDBsum; 2XEJ; -. DR PDBsum; 3BHX; -. DR PDBsum; 3BI0; -. DR PDBsum; 3BI1; -. DR PDBsum; 3BXM; -. DR PDBsum; 3D7D; -. DR PDBsum; 3D7F; -. DR PDBsum; 3D7G; -. DR PDBsum; 3D7H; -. DR PDBsum; 3IWW; -. DR PDBsum; 3RBU; -. DR PDBsum; 3SJE; -. DR PDBsum; 3SJF; -. DR PDBsum; 3SJG; -. DR PDBsum; 3SJX; -. DR PDBsum; 4JYW; -. DR PDBsum; 4JZ0; -. DR PDBsum; 4LQG; -. DR PDBsum; 4MCP; -. DR PDBsum; 4MCQ; -. DR PDBsum; 4MCR; -. DR PDBsum; 4MCS; -. DR PDBsum; 4NGM; -. DR PDBsum; 4NGN; -. DR PDBsum; 4NGP; -. DR PDBsum; 4NGQ; -. DR PDBsum; 4NGR; -. DR PDBsum; 4NGS; -. DR PDBsum; 4NGT; -. DR PDBsum; 4OC0; -. DR PDBsum; 4OC1; -. DR PDBsum; 4OC2; -. DR PDBsum; 4OC3; -. DR PDBsum; 4OC4; -. DR PDBsum; 4OC5; -. DR PDBsum; 4OME; -. DR PDBsum; 4P44; -. DR PDBsum; 4P45; -. DR PDBsum; 4P4B; -. DR PDBsum; 4P4D; -. DR PDBsum; 4P4E; -. DR PDBsum; 4P4F; -. DR PDBsum; 4P4I; -. DR PDBsum; 4P4J; -. DR PDBsum; 4W9Y; -. DR PDBsum; 4X3R; -. DR PDBsum; 5D29; -. DR PDBsum; 5ELY; -. DR PDBsum; 5F09; -. DR PDBsum; 5O5R; -. DR PDBsum; 5O5T; -. DR PDBsum; 5O5U; -. DR PDBsum; 5OF0; -. DR PDBsum; 6ETY; -. DR PDBsum; 6EZ9; -. DR PDBsum; 6F5L; -. DR PDBsum; 6FE5; -. DR PDBsum; 6H7Y; -. DR PDBsum; 6H7Z; -. DR PDBsum; 6HKJ; -. DR PDBsum; 6HKZ; -. DR PDBsum; 6RBC; -. DR PDBsum; 6RTI; -. DR PDBsum; 6S1X; -. DR PDBsum; 6SGP; -. DR PDBsum; 6SKH; -. DR PDBsum; 7BFZ; -. DR PDBsum; 8BO8; -. DR PDBsum; 8BOL; -. DR PDBsum; 8BOW; -. DR PDBsum; 9HLW; -. DR PDBsum; 9HVI; -. DR PDBsum; 9HVK; -. DR PDBsum; 9HVL; -. DR AlphaFoldDB; Q04609; -. DR EMDB; EMD-52273; -. DR EMDB; EMD-52435; -. DR EMDB; EMD-52436; -. DR EMDB; EMD-52437; -. DR EMDB; EMD-52439; -. DR SMR; Q04609; -. DR BioGRID; 108630; 25. DR CORUM; Q04609; -. DR FunCoup; Q04609; 160. DR IntAct; Q04609; 11. DR MINT; Q04609; -. DR STRING; 9606.ENSP00000256999; -. DR BindingDB; Q04609; -. DR ChEMBL; CHEMBL1892; -. DR DrugBank; DB06928; (2S)-2-{[HYDROXY(4-IODOBENZYL)PHOSPHORYL]METHYL}PENTANEDIOIC ACID. DR DrugBank; DB00089; Capromab pendetide. DR DrugBank; DB07754; DCFBC. DR DrugBank; DB17851; Flotufolastat F-18. DR DrugBank; DB16019; Gallium Ga-68 gozetotide. DR DrugBank; DB00142; Glutamic acid. DR DrugBank; DB12514; Iofolastat I-123. DR DrugBank; DB11813; Mipsagargin. DR DrugBank; DB14805; Piflufolastat F 18. DR DrugBank; DB02999; Quisqualic acid. DR DrugBank; DB08835; Spaglumic acid. DR DrugCentral; Q04609; -. DR GuidetoPHARMACOLOGY; 1606; -. DR MEROPS; M28.010; -. DR TCDB; 9.B.229.1.8; the transferrin receptor, cd71, (tfr) family. DR GlyCosmos; Q04609; 10 sites, No reported glycans. DR GlyGen; Q04609; 13 sites, 43 N-linked glycans (7 sites). DR iPTMnet; Q04609; -. DR PhosphoSitePlus; Q04609; -. DR SwissPalm; Q04609; -. DR BioMuta; FOLH1; -. DR DMDM; 548615; -. DR CPTAC; CPTAC-1491; -. DR jPOST; Q04609; -. DR MassIVE; Q04609; -. DR PaxDb; 9606-ENSP00000256999; -. DR PeptideAtlas; Q04609; -. DR ProteomicsDB; 58243; -. [Q04609-1] DR ProteomicsDB; 58244; -. [Q04609-3] DR ProteomicsDB; 58245; -. [Q04609-4] DR ProteomicsDB; 58246; -. [Q04609-6] DR ProteomicsDB; 58247; -. [Q04609-7] DR ProteomicsDB; 58248; -. [Q04609-8] DR ProteomicsDB; 58249; -. [Q04609-9] DR ProteomicsDB; 6482; -. DR ABCD; Q04609; 39 sequenced antibodies. DR Antibodypedia; 2262; 1441 antibodies from 42 providers. DR DNASU; 2346; -. DR Ensembl; ENST00000256999.7; ENSP00000256999.2; ENSG00000086205.19. [Q04609-1] DR Ensembl; ENST00000340334.11; ENSP00000344131.7; ENSG00000086205.19. [Q04609-7] DR Ensembl; ENST00000356696.7; ENSP00000349129.3; ENSG00000086205.19. [Q04609-8] DR Ensembl; ENST00000533034.1; ENSP00000431463.1; ENSG00000086205.19. [Q04609-9] DR GeneID; 2346; -. DR KEGG; hsa:2346; -. DR MANE-Select; ENST00000256999.7; ENSP00000256999.2; NM_004476.3; NP_004467.1. DR UCSC; uc001ngy.3; human. [Q04609-1] DR AGR; HGNC:3788; -. DR ClinPGx; PA28205; -. DR CTD; 2346; -. DR DisGeNET; 2346; -. DR GeneCards; FOLH1; -. DR HGNC; HGNC:3788; FOLH1. DR HPA; ENSG00000086205; Tissue enhanced (intestine, prostate). DR MIM; 600934; gene. DR OpenTargets; ENSG00000086205; -. DR VEuPathDB; HostDB:ENSG00000086205; -. DR eggNOG; KOG2195; Eukaryota. DR GeneTree; ENSGT01030000234598; -. DR HOGENOM; CLU_005688_3_2_1; -. DR InParanoid; Q04609; -. DR OMA; LWNVIGT; -. DR OrthoDB; 5841748at2759; -. DR PAN-GO; Q04609; 2 GO annotations based on evolutionary models. DR PhylomeDB; Q04609; -. DR BRENDA; 3.4.17.21; 2681. DR PathwayCommons; Q04609; -. DR Reactome; R-HSA-8963693; Aspartate and asparagine metabolism. DR SignaLink; Q04609; -. DR Agora; ENSG00000086205; -. DR BioGRID-ORCS; 2346; 20 hits in 1153 CRISPR screens. DR ChiTaRS; FOLH1; human. DR EvolutionaryTrace; Q04609; -. DR GeneWiki; Glutamate_carboxypeptidase_II; -. DR GenomeRNAi; 2346; -. DR Pharos; Q04609; Tclin. DR PRO; PR:Q04609; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; Q04609; protein. DR Bgee; ENSG00000086205; Expressed in duodenum and 102 other cell types or tissues. DR ExpressionAtlas; Q04609; baseline and differential. DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL. DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0016020; C:membrane; TAS:ProtInc. DR GO; GO:0005886; C:plasma membrane; IDA:BHF-UCL. DR GO; GO:1904492; F:Ac-Asp-Glu binding; IDA:BHF-UCL. DR GO; GO:0004180; F:carboxypeptidase activity; IBA:GO_Central. DR GO; GO:0016805; F:dipeptidase activity; IEA:UniProtKB-KW. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0004181; F:metallocarboxypeptidase activity; IDA:BHF-UCL. DR GO; GO:0008233; F:peptidase activity; NAS:UniProtKB. DR GO; GO:1904493; F:tetrahydrofolyl-poly(glutamate) polymer binding; IDA:BHF-UCL. DR GO; GO:0006760; P:folic acid-containing compound metabolic process; IEA:Ensembl. DR GO; GO:0006537; P:glutamate biosynthetic process; IDA:BHF-UCL. DR GO; GO:0098829; P:intestinal folate absorption; IDA:BHF-UCL. DR GO; GO:1900451; P:positive regulation of glutamate receptor signaling pathway; TAS:BHF-UCL. DR GO; GO:0006508; P:proteolysis; IDA:BHF-UCL. DR CDD; cd08022; M28_PSMA_like; 1. DR CDD; cd02121; PA_GCPII_like; 1. DR FunFam; 3.40.630.10:FF:000059; Glutamate carboxypeptidase 2; 1. DR FunFam; 1.20.930.40:FF:000001; N-acetylated-alpha-linked acidic dipeptidase 2; 1. DR FunFam; 3.50.30.30:FF:000002; N-acetylated-alpha-linked acidic dipeptidase 2; 1. DR Gene3D; 3.50.30.30; -; 1. DR Gene3D; 1.20.930.40; Transferrin receptor-like, dimerisation domain; 1. DR Gene3D; 3.40.630.10; Zn peptidases; 1. DR InterPro; IPR046450; PA_dom_sf. DR InterPro; IPR003137; PA_domain. DR InterPro; IPR007484; Peptidase_M28. DR InterPro; IPR039373; Peptidase_M28B. DR InterPro; IPR007365; TFR-like_dimer_dom. DR InterPro; IPR036757; TFR-like_dimer_dom_sf. DR PANTHER; PTHR10404:SF36; GLUTAMATE CARBOXYPEPTIDASE 2; 1. DR PANTHER; PTHR10404; N-ACETYLATED-ALPHA-LINKED ACIDIC DIPEPTIDASE; 1. DR Pfam; PF02225; PA; 1. DR Pfam; PF04389; Peptidase_M28; 1. DR Pfam; PF04253; TFR_dimer; 1. DR SUPFAM; SSF52025; PA domain; 1. DR SUPFAM; SSF47672; Transferrin receptor-like dimerisation domain; 1. DR SUPFAM; SSF53187; Zn-dependent exopeptidases; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Calcium; Carboxypeptidase; KW Cell membrane; Cytoplasm; Dipeptidase; Direct protein sequencing; KW Glycoprotein; Hydrolase; Membrane; Metal-binding; Metalloprotease; KW Multifunctional enzyme; Phosphoprotein; Protease; KW Proteomics identification; Reference proteome; Signal-anchor; KW Transmembrane; Transmembrane helix; Zinc. FT CHAIN 1..750 FT /note="Glutamate carboxypeptidase 2" FT /id="PRO_0000174117" FT TOPO_DOM 1..19 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 20..43 FT /note="Helical; Signal-anchor for type II membrane protein" FT /evidence="ECO:0000305" FT TOPO_DOM 44..750 FT /note="Extracellular" FT /evidence="ECO:0000305" FT REGION 274..587 FT /note="NAALADase" FT ACT_SITE 424 FT /note="Nucleophile; for NAALADase activity" FT ACT_SITE 628 FT /note="Charge relay system" FT /evidence="ECO:0000255" FT ACT_SITE 666 FT /note="Charge relay system" FT /evidence="ECO:0000255" FT ACT_SITE 689 FT /note="Charge relay system" FT /evidence="ECO:0000255" FT BINDING 210 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:16467855, FT ECO:0000269|PubMed:17372356, ECO:0000269|PubMed:17567119, FT ECO:0000269|PubMed:18234225, ECO:0000269|PubMed:19053759, FT ECO:0000269|PubMed:19301871, ECO:0007744|PDB:2C6C, FT ECO:0007744|PDB:2C6G, ECO:0007744|PDB:2JBJ, FT ECO:0007744|PDB:2JBK, ECO:0007744|PDB:2OR4, FT ECO:0007744|PDB:2PVW, ECO:0007744|PDB:2XEF, FT ECO:0007744|PDB:2XEG, ECO:0007744|PDB:2XEI, FT ECO:0007744|PDB:2XEJ, ECO:0007744|PDB:3BHX, FT ECO:0007744|PDB:3BI0, ECO:0007744|PDB:3BI1, FT ECO:0007744|PDB:3D7D, ECO:0007744|PDB:3D7F, FT ECO:0007744|PDB:3D7G, ECO:0007744|PDB:3D7H, FT ECO:0007744|PDB:3IWW, ECO:0007744|PDB:3RBU, FT ECO:0007744|PDB:3SJE, ECO:0007744|PDB:3SJF, FT ECO:0007744|PDB:3SJG, ECO:0007744|PDB:3SJX, FT ECO:0007744|PDB:4JZ0, ECO:0007744|PDB:4LQG, FT ECO:0007744|PDB:4MCP, ECO:0007744|PDB:4MCQ, FT ECO:0007744|PDB:4MCR, ECO:0007744|PDB:4MCS, FT ECO:0007744|PDB:4NGM, ECO:0007744|PDB:4NGN, FT ECO:0007744|PDB:4NGP, ECO:0007744|PDB:4NGQ, FT ECO:0007744|PDB:4NGR, ECO:0007744|PDB:4NGS, FT ECO:0007744|PDB:4NGT, ECO:0007744|PDB:4OC0, FT ECO:0007744|PDB:4OC1, ECO:0007744|PDB:4OC2, FT ECO:0007744|PDB:4OC3, ECO:0007744|PDB:4OC4, FT ECO:0007744|PDB:4OC5, ECO:0007744|PDB:4OME, FT ECO:0007744|PDB:4P44, ECO:0007744|PDB:4P45, FT ECO:0007744|PDB:4P4B, ECO:0007744|PDB:4P4D, FT ECO:0007744|PDB:4P4E, ECO:0007744|PDB:4P4F, FT ECO:0007744|PDB:4P4I, ECO:0007744|PDB:4P4J" FT BINDING 257 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:16467855, FT ECO:0000269|PubMed:17372356, ECO:0000269|PubMed:17567119, FT ECO:0000269|PubMed:18234225, ECO:0000269|PubMed:19053759, FT ECO:0000269|PubMed:19301871, ECO:0007744|PDB:2C6C, FT ECO:0007744|PDB:2C6G, ECO:0007744|PDB:2JBJ, FT ECO:0007744|PDB:2JBK, ECO:0007744|PDB:2OR4, FT ECO:0007744|PDB:2PVW, ECO:0007744|PDB:2XEF, FT ECO:0007744|PDB:2XEG, ECO:0007744|PDB:2XEI, FT ECO:0007744|PDB:2XEJ, ECO:0007744|PDB:3BHX, FT ECO:0007744|PDB:3BI0, ECO:0007744|PDB:3BI1, FT ECO:0007744|PDB:3D7D, ECO:0007744|PDB:3D7F, FT ECO:0007744|PDB:3D7G, ECO:0007744|PDB:3D7H, FT ECO:0007744|PDB:3RBU, ECO:0007744|PDB:3SJX, FT ECO:0007744|PDB:4JYW, ECO:0007744|PDB:4JZ0, FT ECO:0007744|PDB:4LQG, ECO:0007744|PDB:4MCP, FT ECO:0007744|PDB:4MCQ, ECO:0007744|PDB:4MCR, FT ECO:0007744|PDB:4MCS, ECO:0007744|PDB:4NGM, FT ECO:0007744|PDB:4NGN, ECO:0007744|PDB:4NGP, FT ECO:0007744|PDB:4NGQ, ECO:0007744|PDB:4NGR, FT ECO:0007744|PDB:4NGS, ECO:0007744|PDB:4NGT, FT ECO:0007744|PDB:4OC1, ECO:0007744|PDB:4OME, FT ECO:0007744|PDB:4P44, ECO:0007744|PDB:4P45, FT ECO:0007744|PDB:4P4B, ECO:0007744|PDB:4P4D, FT ECO:0007744|PDB:4P4E, ECO:0007744|PDB:4P4F, FT ECO:0007744|PDB:4P4I, ECO:0007744|PDB:4P4J" FT BINDING 269 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000269|PubMed:16467855, FT ECO:0000269|PubMed:17372356, ECO:0000269|PubMed:17567119, FT ECO:0000269|PubMed:18234225, ECO:0000269|PubMed:19053759, FT ECO:0000269|PubMed:19301871, ECO:0007744|PDB:2C6C, FT ECO:0007744|PDB:2C6G, ECO:0007744|PDB:2C6P, FT ECO:0007744|PDB:2CIJ, ECO:0007744|PDB:2JBJ, FT ECO:0007744|PDB:2JBK, ECO:0007744|PDB:2OOT, FT ECO:0007744|PDB:2OR4, ECO:0007744|PDB:2PVV, FT ECO:0007744|PDB:2PVW, ECO:0007744|PDB:2XEF, FT ECO:0007744|PDB:2XEG, ECO:0007744|PDB:2XEI, FT ECO:0007744|PDB:2XEJ, ECO:0007744|PDB:3BHX, FT ECO:0007744|PDB:3BI0, ECO:0007744|PDB:3BI1, FT ECO:0007744|PDB:3BXM, ECO:0007744|PDB:3D7D, FT ECO:0007744|PDB:3D7F, ECO:0007744|PDB:3D7G, FT ECO:0007744|PDB:3D7H, ECO:0007744|PDB:3IWW, FT ECO:0007744|PDB:3RBU, ECO:0007744|PDB:3SJE, FT ECO:0007744|PDB:3SJF, ECO:0007744|PDB:3SJG, FT ECO:0007744|PDB:3SJX, ECO:0007744|PDB:4JYW, FT ECO:0007744|PDB:4JZ0, ECO:0007744|PDB:4LQG, FT ECO:0007744|PDB:4MCP, ECO:0007744|PDB:4MCQ, FT ECO:0007744|PDB:4MCR, ECO:0007744|PDB:4MCS, FT ECO:0007744|PDB:4NGM, ECO:0007744|PDB:4NGN, FT ECO:0007744|PDB:4NGP, ECO:0007744|PDB:4NGQ, FT ECO:0007744|PDB:4NGR, ECO:0007744|PDB:4NGS, FT ECO:0007744|PDB:4NGT, ECO:0007744|PDB:4OC0, FT ECO:0007744|PDB:4OC1, ECO:0007744|PDB:4OC2, FT ECO:0007744|PDB:4OC3, ECO:0007744|PDB:4OC4, FT ECO:0007744|PDB:4OC5, ECO:0007744|PDB:4OME, FT ECO:0007744|PDB:4P44, ECO:0007744|PDB:4P45, FT ECO:0007744|PDB:4P4B, ECO:0007744|PDB:4P4D, FT ECO:0007744|PDB:4P4E, ECO:0007744|PDB:4P4F, FT ECO:0007744|PDB:4P4I, ECO:0007744|PDB:4P4J" FT BINDING 272 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000269|PubMed:16467855, FT ECO:0000269|PubMed:17372356, ECO:0000269|PubMed:17567119, FT ECO:0000269|PubMed:18234225, ECO:0000269|PubMed:19053759, FT ECO:0000269|PubMed:19301871, ECO:0007744|PDB:2C6C, FT ECO:0007744|PDB:2C6G, ECO:0007744|PDB:2C6P, FT ECO:0007744|PDB:2CIJ, ECO:0007744|PDB:2JBJ, FT ECO:0007744|PDB:2JBK, ECO:0007744|PDB:2OOT, FT ECO:0007744|PDB:2OR4, ECO:0007744|PDB:2PVV, FT ECO:0007744|PDB:2PVW, ECO:0007744|PDB:2XEF, FT ECO:0007744|PDB:2XEG, ECO:0007744|PDB:2XEI, FT ECO:0007744|PDB:2XEJ, ECO:0007744|PDB:3BHX, FT ECO:0007744|PDB:3BI0, ECO:0007744|PDB:3BI1, FT ECO:0007744|PDB:3BXM, ECO:0007744|PDB:3D7D, FT ECO:0007744|PDB:3D7F, ECO:0007744|PDB:3D7G, FT ECO:0007744|PDB:3D7H, ECO:0007744|PDB:3IWW, FT ECO:0007744|PDB:3RBU, ECO:0007744|PDB:3SJE, FT ECO:0007744|PDB:3SJF, ECO:0007744|PDB:3SJG, FT ECO:0007744|PDB:3SJX, ECO:0007744|PDB:4JYW, FT ECO:0007744|PDB:4JZ0, ECO:0007744|PDB:4LQG, FT ECO:0007744|PDB:4MCP, ECO:0007744|PDB:4MCQ, FT ECO:0007744|PDB:4MCR, ECO:0007744|PDB:4MCS, FT ECO:0007744|PDB:4NGM, ECO:0007744|PDB:4NGN, FT ECO:0007744|PDB:4NGP, ECO:0007744|PDB:4NGQ, FT ECO:0007744|PDB:4NGR, ECO:0007744|PDB:4NGS, FT ECO:0007744|PDB:4NGT, ECO:0007744|PDB:4OC0, FT ECO:0007744|PDB:4OC1, ECO:0007744|PDB:4OC2, FT ECO:0007744|PDB:4OC3, ECO:0007744|PDB:4OC4, FT ECO:0007744|PDB:4OC5, ECO:0007744|PDB:4OME, FT ECO:0007744|PDB:4P44, ECO:0007744|PDB:4P45, FT ECO:0007744|PDB:4P4B, ECO:0007744|PDB:4P4D, FT ECO:0007744|PDB:4P4E, ECO:0007744|PDB:4P4F, FT ECO:0007744|PDB:4P4I, ECO:0007744|PDB:4P4J" FT BINDING 377 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:16467855, FT ECO:0000269|PubMed:17372356, ECO:0000269|PubMed:17567119, FT ECO:0000269|PubMed:18234225, ECO:0000269|PubMed:19053759, FT ECO:0000269|PubMed:19301871, ECO:0007744|PDB:1Z8L, FT ECO:0007744|PDB:2C6C, ECO:0007744|PDB:2C6G, FT ECO:0007744|PDB:2C6P, ECO:0007744|PDB:2CIJ, FT ECO:0007744|PDB:2JBJ, ECO:0007744|PDB:2JBK, FT ECO:0007744|PDB:2OOT, ECO:0007744|PDB:2OR4, FT ECO:0007744|PDB:2PVV, ECO:0007744|PDB:2PVW, FT ECO:0007744|PDB:2XEF, ECO:0007744|PDB:2XEG, FT ECO:0007744|PDB:2XEI, ECO:0007744|PDB:2XEJ, FT ECO:0007744|PDB:3BHX, ECO:0007744|PDB:3BI0, FT ECO:0007744|PDB:3BI1, ECO:0007744|PDB:3BXM, FT ECO:0007744|PDB:3D7D, ECO:0007744|PDB:3D7F, FT ECO:0007744|PDB:3D7G, ECO:0007744|PDB:3D7H, FT ECO:0007744|PDB:3IWW, ECO:0007744|PDB:3RBU, FT ECO:0007744|PDB:3SJE, ECO:0007744|PDB:3SJF, FT ECO:0007744|PDB:3SJG, ECO:0007744|PDB:3SJX, FT ECO:0007744|PDB:4JYW, ECO:0007744|PDB:4JZ0, FT ECO:0007744|PDB:4LQG, ECO:0007744|PDB:4MCP, FT ECO:0007744|PDB:4MCQ, ECO:0007744|PDB:4MCR, FT ECO:0007744|PDB:4MCS, ECO:0007744|PDB:4NGM, FT ECO:0007744|PDB:4NGN, ECO:0007744|PDB:4NGP, FT ECO:0007744|PDB:4NGQ, ECO:0007744|PDB:4NGR, FT ECO:0007744|PDB:4NGS, ECO:0007744|PDB:4NGT, FT ECO:0007744|PDB:4OC0, ECO:0007744|PDB:4OC1, FT ECO:0007744|PDB:4OC2, ECO:0007744|PDB:4OC3, FT ECO:0007744|PDB:4OC4, ECO:0007744|PDB:4OC5, FT ECO:0007744|PDB:4OME, ECO:0007744|PDB:4P44, FT ECO:0007744|PDB:4P45, ECO:0007744|PDB:4P4B, FT ECO:0007744|PDB:4P4D, ECO:0007744|PDB:4P4E, FT ECO:0007744|PDB:4P4F, ECO:0007744|PDB:4P4I, FT ECO:0007744|PDB:4P4J" FT BINDING 387 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:16467855, FT ECO:0000269|PubMed:17372356, ECO:0000269|PubMed:17567119, FT ECO:0000269|PubMed:18234225, ECO:0000269|PubMed:19053759, FT ECO:0000269|PubMed:19301871, ECO:0007744|PDB:1Z8L, FT ECO:0007744|PDB:2C6C, ECO:0007744|PDB:2C6G, FT ECO:0007744|PDB:2C6P, ECO:0007744|PDB:2CIJ, FT ECO:0007744|PDB:2JBJ, ECO:0007744|PDB:2JBK, FT ECO:0007744|PDB:2OOT, ECO:0007744|PDB:2OR4, FT ECO:0007744|PDB:2PVV, ECO:0007744|PDB:2PVW, FT ECO:0007744|PDB:2XEF, ECO:0007744|PDB:2XEG, FT ECO:0007744|PDB:2XEI, ECO:0007744|PDB:2XEJ, FT ECO:0007744|PDB:3BHX, ECO:0007744|PDB:3BI0, FT ECO:0007744|PDB:3BI1, ECO:0007744|PDB:3BXM, FT ECO:0007744|PDB:3D7D, ECO:0007744|PDB:3D7F, FT ECO:0007744|PDB:3D7G, ECO:0007744|PDB:3D7H, FT ECO:0007744|PDB:3IWW, ECO:0007744|PDB:3RBU, FT ECO:0007744|PDB:3SJE, ECO:0007744|PDB:3SJF, FT ECO:0007744|PDB:3SJG, ECO:0007744|PDB:3SJX, FT ECO:0007744|PDB:4JYW, ECO:0007744|PDB:4JZ0, FT ECO:0007744|PDB:4LQG, ECO:0007744|PDB:4MCP, FT ECO:0007744|PDB:4MCQ, ECO:0007744|PDB:4MCR, FT ECO:0007744|PDB:4MCS, ECO:0007744|PDB:4NGM, FT ECO:0007744|PDB:4NGN, ECO:0007744|PDB:4NGP, FT ECO:0007744|PDB:4NGQ, ECO:0007744|PDB:4NGR, FT ECO:0007744|PDB:4NGS, ECO:0007744|PDB:4NGT, FT ECO:0007744|PDB:4OC0, ECO:0007744|PDB:4OC1, FT ECO:0007744|PDB:4OC2, ECO:0007744|PDB:4OC3, FT ECO:0007744|PDB:4OC4, ECO:0007744|PDB:4OC5, FT ECO:0007744|PDB:4OME, ECO:0007744|PDB:4P44, FT ECO:0007744|PDB:4P45, ECO:0007744|PDB:4P4B, FT ECO:0007744|PDB:4P4D, ECO:0007744|PDB:4P4E, FT ECO:0007744|PDB:4P4F, ECO:0007744|PDB:4P4I, FT ECO:0007744|PDB:4P4J" FT BINDING 387 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:16467855, FT ECO:0000269|PubMed:17372356, ECO:0000269|PubMed:17567119, FT ECO:0000269|PubMed:18234225, ECO:0000269|PubMed:19053759, FT ECO:0000269|PubMed:19301871, ECO:0007744|PDB:1Z8L, FT ECO:0007744|PDB:2C6C, ECO:0007744|PDB:2C6G, FT ECO:0007744|PDB:2C6P, ECO:0007744|PDB:2CIJ, FT ECO:0007744|PDB:2JBJ, ECO:0007744|PDB:2JBK, FT ECO:0007744|PDB:2OOT, ECO:0007744|PDB:2OR4, FT ECO:0007744|PDB:2PVV, ECO:0007744|PDB:2PVW, FT ECO:0007744|PDB:2XEF, ECO:0007744|PDB:2XEG, FT ECO:0007744|PDB:2XEI, ECO:0007744|PDB:2XEJ, FT ECO:0007744|PDB:3BHX, ECO:0007744|PDB:3BI0, FT ECO:0007744|PDB:3BI1, ECO:0007744|PDB:3BXM, FT ECO:0007744|PDB:3D7D, ECO:0007744|PDB:3D7F, FT ECO:0007744|PDB:3D7G, ECO:0007744|PDB:3D7H, FT ECO:0007744|PDB:3IWW, ECO:0007744|PDB:3RBU, FT ECO:0007744|PDB:3SJE, ECO:0007744|PDB:3SJF, FT ECO:0007744|PDB:3SJG, ECO:0007744|PDB:3SJX, FT ECO:0007744|PDB:4JYW, ECO:0007744|PDB:4JZ0, FT ECO:0007744|PDB:4LQG, ECO:0007744|PDB:4MCP, FT ECO:0007744|PDB:4MCQ, ECO:0007744|PDB:4MCR, FT ECO:0007744|PDB:4MCS, ECO:0007744|PDB:4NGM, FT ECO:0007744|PDB:4NGN, ECO:0007744|PDB:4NGP, FT ECO:0007744|PDB:4NGQ, ECO:0007744|PDB:4NGR, FT ECO:0007744|PDB:4NGS, ECO:0007744|PDB:4NGT, FT ECO:0007744|PDB:4OC0, ECO:0007744|PDB:4OC1, FT ECO:0007744|PDB:4OC2, ECO:0007744|PDB:4OC3, FT ECO:0007744|PDB:4OC4, ECO:0007744|PDB:4OC5, FT ECO:0007744|PDB:4OME, ECO:0007744|PDB:4P44, FT ECO:0007744|PDB:4P45, ECO:0007744|PDB:4P4B, FT ECO:0007744|PDB:4P4D, ECO:0007744|PDB:4P4E, FT ECO:0007744|PDB:4P4F, ECO:0007744|PDB:4P4I, FT ECO:0007744|PDB:4P4J" FT BINDING 424 FT /ligand="substrate" FT /evidence="ECO:0000250|UniProtKB:Q9Y3Q0" FT BINDING 425 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:16467855, FT ECO:0000269|PubMed:17372356, ECO:0000269|PubMed:17567119, FT ECO:0000269|PubMed:18234225, ECO:0000269|PubMed:19053759, FT ECO:0000269|PubMed:19301871, ECO:0007744|PDB:1Z8L, FT ECO:0007744|PDB:2C6C, ECO:0007744|PDB:2C6G, FT ECO:0007744|PDB:2C6P, ECO:0007744|PDB:2CIJ, FT ECO:0007744|PDB:2JBJ, ECO:0007744|PDB:2JBK, FT ECO:0007744|PDB:2OOT, ECO:0007744|PDB:2OR4, FT ECO:0007744|PDB:2PVV, ECO:0007744|PDB:2PVW, FT ECO:0007744|PDB:2XEF, ECO:0007744|PDB:2XEG, FT ECO:0007744|PDB:2XEI, ECO:0007744|PDB:2XEJ, FT ECO:0007744|PDB:3BHX, ECO:0007744|PDB:3BI0, FT ECO:0007744|PDB:3BI1, ECO:0007744|PDB:3BXM, FT ECO:0007744|PDB:3D7D, ECO:0007744|PDB:3D7F, FT ECO:0007744|PDB:3D7G, ECO:0007744|PDB:3D7H, FT ECO:0007744|PDB:3IWW, ECO:0007744|PDB:3RBU, FT ECO:0007744|PDB:3SJE, ECO:0007744|PDB:3SJF, FT ECO:0007744|PDB:3SJG, ECO:0007744|PDB:3SJX, FT ECO:0007744|PDB:4JYW, ECO:0007744|PDB:4JZ0, FT ECO:0007744|PDB:4LQG, ECO:0007744|PDB:4MCP, FT ECO:0007744|PDB:4MCQ, ECO:0007744|PDB:4MCR, FT ECO:0007744|PDB:4MCS, ECO:0007744|PDB:4NGM, FT ECO:0007744|PDB:4NGN, ECO:0007744|PDB:4NGP, FT ECO:0007744|PDB:4NGQ, ECO:0007744|PDB:4NGR, FT ECO:0007744|PDB:4NGS, ECO:0007744|PDB:4NGT, FT ECO:0007744|PDB:4OC0, ECO:0007744|PDB:4OC1, FT ECO:0007744|PDB:4OC2, ECO:0007744|PDB:4OC3, FT ECO:0007744|PDB:4OC4, ECO:0007744|PDB:4OC5, FT ECO:0007744|PDB:4OME, ECO:0007744|PDB:4P44, FT ECO:0007744|PDB:4P45, ECO:0007744|PDB:4P4B, FT ECO:0007744|PDB:4P4D, ECO:0007744|PDB:4P4E, FT ECO:0007744|PDB:4P4F, ECO:0007744|PDB:4P4I, FT ECO:0007744|PDB:4P4J" FT BINDING 433 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000269|PubMed:16467855, FT ECO:0000269|PubMed:17372356, ECO:0000269|PubMed:17567119, FT ECO:0000269|PubMed:18234225, ECO:0000269|PubMed:19053759, FT ECO:0000269|PubMed:19301871, ECO:0007744|PDB:2C6C, FT ECO:0007744|PDB:2C6G, ECO:0007744|PDB:2C6P, FT ECO:0007744|PDB:2CIJ, ECO:0007744|PDB:2JBJ, FT ECO:0007744|PDB:2JBK, ECO:0007744|PDB:2OOT, FT ECO:0007744|PDB:2OR4, ECO:0007744|PDB:2PVV, FT ECO:0007744|PDB:2PVW, ECO:0007744|PDB:2XEF, FT ECO:0007744|PDB:2XEG, ECO:0007744|PDB:2XEI, FT ECO:0007744|PDB:2XEJ, ECO:0007744|PDB:3BHX, FT ECO:0007744|PDB:3BI0, ECO:0007744|PDB:3BI1, FT ECO:0007744|PDB:3BXM, ECO:0007744|PDB:3D7D, FT ECO:0007744|PDB:3D7F, ECO:0007744|PDB:3D7G, FT ECO:0007744|PDB:3D7H, ECO:0007744|PDB:3IWW, FT ECO:0007744|PDB:3RBU, ECO:0007744|PDB:3SJE, FT ECO:0007744|PDB:3SJF, ECO:0007744|PDB:3SJG, FT ECO:0007744|PDB:3SJX, ECO:0007744|PDB:4JYW, FT ECO:0007744|PDB:4JZ0, ECO:0007744|PDB:4LQG, FT ECO:0007744|PDB:4MCP, ECO:0007744|PDB:4MCQ, FT ECO:0007744|PDB:4MCR, ECO:0007744|PDB:4MCS, FT ECO:0007744|PDB:4NGM, ECO:0007744|PDB:4NGN, FT ECO:0007744|PDB:4NGP, ECO:0007744|PDB:4NGQ, FT ECO:0007744|PDB:4NGR, ECO:0007744|PDB:4NGS, FT ECO:0007744|PDB:4NGT, ECO:0007744|PDB:4OC0, FT ECO:0007744|PDB:4OC1, ECO:0007744|PDB:4OC2, FT ECO:0007744|PDB:4OC3, ECO:0007744|PDB:4OC4, FT ECO:0007744|PDB:4OC5, ECO:0007744|PDB:4OME, FT ECO:0007744|PDB:4P44, ECO:0007744|PDB:4P45, FT ECO:0007744|PDB:4P4B, ECO:0007744|PDB:4P4D, FT ECO:0007744|PDB:4P4E, ECO:0007744|PDB:4P4F, FT ECO:0007744|PDB:4P4I, ECO:0007744|PDB:4P4J" FT BINDING 436 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000269|PubMed:16467855, FT ECO:0000269|PubMed:17372356, ECO:0000269|PubMed:17567119, FT ECO:0000269|PubMed:18234225, ECO:0000269|PubMed:19053759, FT ECO:0000269|PubMed:19301871, ECO:0007744|PDB:2C6C, FT ECO:0007744|PDB:2C6G, ECO:0007744|PDB:2C6P, FT ECO:0007744|PDB:2CIJ, ECO:0007744|PDB:2JBJ, FT ECO:0007744|PDB:2JBK, ECO:0007744|PDB:2OOT, FT ECO:0007744|PDB:2OR4, ECO:0007744|PDB:2PVV, FT ECO:0007744|PDB:2PVW, ECO:0007744|PDB:2XEF, FT ECO:0007744|PDB:2XEG, ECO:0007744|PDB:2XEI, FT ECO:0007744|PDB:2XEJ, ECO:0007744|PDB:3BHX, FT ECO:0007744|PDB:3BI0, ECO:0007744|PDB:3BI1, FT ECO:0007744|PDB:3BXM, ECO:0007744|PDB:3D7D, FT ECO:0007744|PDB:3D7F, ECO:0007744|PDB:3D7G, FT ECO:0007744|PDB:3D7H, ECO:0007744|PDB:3IWW, FT ECO:0007744|PDB:3RBU, ECO:0007744|PDB:3SJE, FT ECO:0007744|PDB:3SJF, ECO:0007744|PDB:3SJG, FT ECO:0007744|PDB:3SJX, ECO:0007744|PDB:4JYW, FT ECO:0007744|PDB:4JZ0, ECO:0007744|PDB:4LQG, FT ECO:0007744|PDB:4MCP, ECO:0007744|PDB:4MCQ, FT ECO:0007744|PDB:4MCR, ECO:0007744|PDB:4MCS, FT ECO:0007744|PDB:4NGM, ECO:0007744|PDB:4NGN, FT ECO:0007744|PDB:4NGP, ECO:0007744|PDB:4NGQ, FT ECO:0007744|PDB:4NGR, ECO:0007744|PDB:4NGS, FT ECO:0007744|PDB:4NGT, ECO:0007744|PDB:4OC0, FT ECO:0007744|PDB:4OC1, ECO:0007744|PDB:4OC2, FT ECO:0007744|PDB:4OC3, ECO:0007744|PDB:4OC4, FT ECO:0007744|PDB:4OC5, ECO:0007744|PDB:4OME, FT ECO:0007744|PDB:4P44, ECO:0007744|PDB:4P45, FT ECO:0007744|PDB:4P4B, ECO:0007744|PDB:4P4D, FT ECO:0007744|PDB:4P4E, ECO:0007744|PDB:4P4F, FT ECO:0007744|PDB:4P4I, ECO:0007744|PDB:4P4J" FT BINDING 453 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:16467855, FT ECO:0000269|PubMed:17372356, ECO:0000269|PubMed:17567119, FT ECO:0000269|PubMed:18234225, ECO:0000269|PubMed:19053759, FT ECO:0000269|PubMed:19301871, ECO:0007744|PDB:1Z8L, FT ECO:0007744|PDB:2C6C, ECO:0007744|PDB:2C6G, FT ECO:0007744|PDB:2C6P, ECO:0007744|PDB:2CIJ, FT ECO:0007744|PDB:2JBJ, ECO:0007744|PDB:2JBK, FT ECO:0007744|PDB:2OOT, ECO:0007744|PDB:2OR4, FT ECO:0007744|PDB:2PVV, ECO:0007744|PDB:2PVW, FT ECO:0007744|PDB:2XEF, ECO:0007744|PDB:2XEG, FT ECO:0007744|PDB:2XEI, ECO:0007744|PDB:2XEJ, FT ECO:0007744|PDB:3BHX, ECO:0007744|PDB:3BI0, FT ECO:0007744|PDB:3BI1, ECO:0007744|PDB:3BXM, FT ECO:0007744|PDB:3D7D, ECO:0007744|PDB:3D7F, FT ECO:0007744|PDB:3D7G, ECO:0007744|PDB:3D7H, FT ECO:0007744|PDB:3IWW, ECO:0007744|PDB:3RBU, FT ECO:0007744|PDB:3SJE, ECO:0007744|PDB:3SJF, FT ECO:0007744|PDB:3SJG, ECO:0007744|PDB:3SJX, FT ECO:0007744|PDB:4JYW, ECO:0007744|PDB:4JZ0, FT ECO:0007744|PDB:4LQG, ECO:0007744|PDB:4MCP, FT ECO:0007744|PDB:4MCQ, ECO:0007744|PDB:4MCR, FT ECO:0007744|PDB:4MCS, ECO:0007744|PDB:4NGM, FT ECO:0007744|PDB:4NGN, ECO:0007744|PDB:4NGP, FT ECO:0007744|PDB:4NGQ, ECO:0007744|PDB:4NGR, FT ECO:0007744|PDB:4NGS, ECO:0007744|PDB:4NGT, FT ECO:0007744|PDB:4OC0, ECO:0007744|PDB:4OC1, FT ECO:0007744|PDB:4OC2, ECO:0007744|PDB:4OC3, FT ECO:0007744|PDB:4OC4, ECO:0007744|PDB:4OC5, FT ECO:0007744|PDB:4OME, ECO:0007744|PDB:4P44, FT ECO:0007744|PDB:4P45, ECO:0007744|PDB:4P4B, FT ECO:0007744|PDB:4P4D, ECO:0007744|PDB:4P4E, FT ECO:0007744|PDB:4P4F, ECO:0007744|PDB:4P4I, FT ECO:0007744|PDB:4P4J" FT BINDING 517..518 FT /ligand="substrate" FT /evidence="ECO:0000250|UniProtKB:Q9Y3Q0" FT BINDING 519 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:16467855, FT ECO:0000269|PubMed:17372356, ECO:0000269|PubMed:17567119, FT ECO:0000269|PubMed:18234225, ECO:0000269|PubMed:19053759, FT ECO:0000269|PubMed:19301871, ECO:0007744|PDB:2C6G, FT ECO:0007744|PDB:2JBJ, ECO:0007744|PDB:2JBK, FT ECO:0007744|PDB:2OR4, ECO:0007744|PDB:2XEF, FT ECO:0007744|PDB:2XEG, ECO:0007744|PDB:2XEI, FT ECO:0007744|PDB:2XEJ, ECO:0007744|PDB:3BHX, FT ECO:0007744|PDB:3BI0, ECO:0007744|PDB:3BI1, FT ECO:0007744|PDB:3D7D, ECO:0007744|PDB:3D7F, FT ECO:0007744|PDB:3D7G, ECO:0007744|PDB:3D7H, FT ECO:0007744|PDB:3IWW, ECO:0007744|PDB:3SJE, FT ECO:0007744|PDB:3SJF, ECO:0007744|PDB:3SJG, FT ECO:0007744|PDB:3SJX, ECO:0007744|PDB:4JZ0, FT ECO:0007744|PDB:4LQG, ECO:0007744|PDB:4MCP, FT ECO:0007744|PDB:4MCQ, ECO:0007744|PDB:4MCR, FT ECO:0007744|PDB:4MCS, ECO:0007744|PDB:4NGM, FT ECO:0007744|PDB:4NGN, ECO:0007744|PDB:4NGP, FT ECO:0007744|PDB:4NGQ, ECO:0007744|PDB:4NGR, FT ECO:0007744|PDB:4NGS, ECO:0007744|PDB:4NGT, FT ECO:0007744|PDB:4OC0, ECO:0007744|PDB:4OC1, FT ECO:0007744|PDB:4OC2, ECO:0007744|PDB:4OC3, FT ECO:0007744|PDB:4OC4, ECO:0007744|PDB:4OC5, FT ECO:0007744|PDB:4OME, ECO:0007744|PDB:4P44, FT ECO:0007744|PDB:4P45, ECO:0007744|PDB:4P4B, FT ECO:0007744|PDB:4P4D, ECO:0007744|PDB:4P4E, FT ECO:0007744|PDB:4P4F, ECO:0007744|PDB:4P4I, FT ECO:0007744|PDB:4P4J" FT BINDING 534..536 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:18234225, FT ECO:0000269|PubMed:19053759, ECO:0007744|PDB:2XEF, FT ECO:0007744|PDB:2XEG, ECO:0007744|PDB:2XEI, FT ECO:0007744|PDB:2XEJ, ECO:0007744|PDB:3BHX, FT ECO:0007744|PDB:3BI0, ECO:0007744|PDB:3BI1, FT ECO:0007744|PDB:3D7D, ECO:0007744|PDB:3D7F, FT ECO:0007744|PDB:3D7G, ECO:0007744|PDB:3D7H, FT ECO:0007744|PDB:3IWW, ECO:0007744|PDB:3SJE, FT ECO:0007744|PDB:3SJF, ECO:0007744|PDB:3SJG, FT ECO:0007744|PDB:3SJX, ECO:0007744|PDB:4JZ0, FT ECO:0007744|PDB:4LQG, ECO:0007744|PDB:4MCP, FT ECO:0007744|PDB:4MCQ, ECO:0007744|PDB:4MCR, FT ECO:0007744|PDB:4MCS, ECO:0007744|PDB:4NGM, FT ECO:0007744|PDB:4NGN, ECO:0007744|PDB:4NGP, FT ECO:0007744|PDB:4NGQ, ECO:0007744|PDB:4NGR, FT ECO:0007744|PDB:4NGS, ECO:0007744|PDB:4NGT, FT ECO:0007744|PDB:4OC0, ECO:0007744|PDB:4OC1, FT ECO:0007744|PDB:4OC2, ECO:0007744|PDB:4OC3, FT ECO:0007744|PDB:4OC4, ECO:0007744|PDB:4OC5, FT ECO:0007744|PDB:4OME, ECO:0007744|PDB:4P44, FT ECO:0007744|PDB:4P45, ECO:0007744|PDB:4P4B, FT ECO:0007744|PDB:4P4D, ECO:0007744|PDB:4P4F, FT ECO:0007744|PDB:4P4I, ECO:0007744|PDB:4P4J" FT BINDING 552..553 FT /ligand="substrate" FT /evidence="ECO:0000250|UniProtKB:Q9Y3Q0" FT BINDING 552 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:16467855, FT ECO:0000269|PubMed:17372356, ECO:0000269|PubMed:17567119, FT ECO:0000269|PubMed:18234225, ECO:0000269|PubMed:19053759, FT ECO:0000269|PubMed:19301871, ECO:0007744|PDB:2C6C, FT ECO:0007744|PDB:2C6G, ECO:0007744|PDB:2JBJ, FT ECO:0007744|PDB:2OR4, ECO:0007744|PDB:2PVW, FT ECO:0007744|PDB:2XEF, ECO:0007744|PDB:2XEG, FT ECO:0007744|PDB:2XEI, ECO:0007744|PDB:2XEJ, FT ECO:0007744|PDB:3BHX, ECO:0007744|PDB:3BI0, FT ECO:0007744|PDB:3BI1, ECO:0007744|PDB:3D7D, FT ECO:0007744|PDB:3D7F, ECO:0007744|PDB:3D7G, FT ECO:0007744|PDB:3D7H, ECO:0007744|PDB:3IWW, FT ECO:0007744|PDB:3RBU, ECO:0007744|PDB:3SJE, FT ECO:0007744|PDB:3SJF, ECO:0007744|PDB:3SJG, FT ECO:0007744|PDB:3SJX, ECO:0007744|PDB:4JYW, FT ECO:0007744|PDB:4JZ0, ECO:0007744|PDB:4LQG, FT ECO:0007744|PDB:4MCP, ECO:0007744|PDB:4MCQ, FT ECO:0007744|PDB:4MCR, ECO:0007744|PDB:4MCS, FT ECO:0007744|PDB:4NGM, ECO:0007744|PDB:4NGN, FT ECO:0007744|PDB:4NGP, ECO:0007744|PDB:4NGQ, FT ECO:0007744|PDB:4NGR, ECO:0007744|PDB:4NGS, FT ECO:0007744|PDB:4NGT, ECO:0007744|PDB:4OC0, FT ECO:0007744|PDB:4OC1, ECO:0007744|PDB:4OC2, FT ECO:0007744|PDB:4OC3, ECO:0007744|PDB:4OC4, FT ECO:0007744|PDB:4OC5, ECO:0007744|PDB:4OME, FT ECO:0007744|PDB:4P44, ECO:0007744|PDB:4P45, FT ECO:0007744|PDB:4P4B, ECO:0007744|PDB:4P4D, FT ECO:0007744|PDB:4P4E, ECO:0007744|PDB:4P4F, FT ECO:0007744|PDB:4P4I, ECO:0007744|PDB:4P4J" FT BINDING 553 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:16467855, FT ECO:0000269|PubMed:17372356, ECO:0000269|PubMed:17567119, FT ECO:0000269|PubMed:18234225, ECO:0000269|PubMed:19053759, FT ECO:0000269|PubMed:19301871, ECO:0007744|PDB:1Z8L, FT ECO:0007744|PDB:2C6C, ECO:0007744|PDB:2C6G, FT ECO:0007744|PDB:2C6P, ECO:0007744|PDB:2CIJ, FT ECO:0007744|PDB:2JBJ, ECO:0007744|PDB:2JBK, FT ECO:0007744|PDB:2OOT, ECO:0007744|PDB:2OR4, FT ECO:0007744|PDB:2PVV, ECO:0007744|PDB:2PVW, FT ECO:0007744|PDB:2XEF, ECO:0007744|PDB:2XEG, FT ECO:0007744|PDB:2XEI, ECO:0007744|PDB:2XEJ, FT ECO:0007744|PDB:3BHX, ECO:0007744|PDB:3BI0, FT ECO:0007744|PDB:3BI1, ECO:0007744|PDB:3BXM, FT ECO:0007744|PDB:3D7D, ECO:0007744|PDB:3D7F, FT ECO:0007744|PDB:3D7G, ECO:0007744|PDB:3D7H, FT ECO:0007744|PDB:3IWW, ECO:0007744|PDB:3RBU, FT ECO:0007744|PDB:3SJE, ECO:0007744|PDB:3SJF, FT ECO:0007744|PDB:3SJG, ECO:0007744|PDB:3SJX, FT ECO:0007744|PDB:4JYW, ECO:0007744|PDB:4JZ0, FT ECO:0007744|PDB:4LQG, ECO:0007744|PDB:4MCP, FT ECO:0007744|PDB:4MCQ, ECO:0007744|PDB:4MCR, FT ECO:0007744|PDB:4MCS, ECO:0007744|PDB:4NGM, FT ECO:0007744|PDB:4NGN, ECO:0007744|PDB:4NGP, FT ECO:0007744|PDB:4NGQ, ECO:0007744|PDB:4NGR, FT ECO:0007744|PDB:4NGS, ECO:0007744|PDB:4NGT, FT ECO:0007744|PDB:4OC0, ECO:0007744|PDB:4OC1, FT ECO:0007744|PDB:4OC2, ECO:0007744|PDB:4OC3, FT ECO:0007744|PDB:4OC4, ECO:0007744|PDB:4OC5, FT ECO:0007744|PDB:4OME, ECO:0007744|PDB:4P44, FT ECO:0007744|PDB:4P45, ECO:0007744|PDB:4P4B, FT ECO:0007744|PDB:4P4D, ECO:0007744|PDB:4P4E, FT ECO:0007744|PDB:4P4F, ECO:0007744|PDB:4P4I, FT ECO:0007744|PDB:4P4J" FT BINDING 699..700 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:16467855, FT ECO:0000269|PubMed:17372356, ECO:0000269|PubMed:17567119, FT ECO:0000269|PubMed:18234225, ECO:0000269|PubMed:19053759, FT ECO:0007744|PDB:2C6C, ECO:0007744|PDB:2C6G, FT ECO:0007744|PDB:2JBJ, ECO:0007744|PDB:2JBK, FT ECO:0007744|PDB:2OR4, ECO:0007744|PDB:2PVW, FT ECO:0007744|PDB:2XEF, ECO:0007744|PDB:2XEG, FT ECO:0007744|PDB:2XEI, ECO:0007744|PDB:2XEJ, FT ECO:0007744|PDB:3BHX, ECO:0007744|PDB:3BI0, FT ECO:0007744|PDB:3BI1, ECO:0007744|PDB:3D7D, FT ECO:0007744|PDB:3D7F, ECO:0007744|PDB:3D7G, FT ECO:0007744|PDB:3D7H, ECO:0007744|PDB:3IWW, FT ECO:0007744|PDB:3RBU, ECO:0007744|PDB:3SJF, FT ECO:0007744|PDB:3SJX, ECO:0007744|PDB:4JYW, FT ECO:0007744|PDB:4JZ0, ECO:0007744|PDB:4LQG, FT ECO:0007744|PDB:4MCP, ECO:0007744|PDB:4MCQ, FT ECO:0007744|PDB:4MCR, ECO:0007744|PDB:4MCS, FT ECO:0007744|PDB:4NGM, ECO:0007744|PDB:4NGN, FT ECO:0007744|PDB:4NGP, ECO:0007744|PDB:4NGQ, FT ECO:0007744|PDB:4NGR, ECO:0007744|PDB:4NGS, FT ECO:0007744|PDB:4NGT, ECO:0007744|PDB:4OC0, FT ECO:0007744|PDB:4OC1, ECO:0007744|PDB:4OC2, FT ECO:0007744|PDB:4OC3, ECO:0007744|PDB:4OC4, FT ECO:0007744|PDB:4OC5, ECO:0007744|PDB:4OME, FT ECO:0007744|PDB:4P44, ECO:0007744|PDB:4P45, FT ECO:0007744|PDB:4P4B, ECO:0007744|PDB:4P4D, FT ECO:0007744|PDB:4P4E, ECO:0007744|PDB:4P4F, FT ECO:0007744|PDB:4P4I, ECO:0007744|PDB:4P4J" FT MOD_RES 10 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P70627" FT CARBOHYD 51 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:15152093" FT CARBOHYD 76 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:12754519, FT ECO:0000269|PubMed:15152093, ECO:0000269|PubMed:16467855, FT ECO:0000269|PubMed:17372356, ECO:0000269|PubMed:17567119, FT ECO:0000269|PubMed:18234225, ECO:0000269|PubMed:19053759, FT ECO:0000269|PubMed:19301871, ECO:0007744|PDB:1Z8L, FT ECO:0007744|PDB:2C6C, ECO:0007744|PDB:2C6G, FT ECO:0007744|PDB:2C6P, ECO:0007744|PDB:2CIJ, FT ECO:0007744|PDB:2JBJ, ECO:0007744|PDB:2JBK, FT ECO:0007744|PDB:2OOT, ECO:0007744|PDB:2OR4, FT ECO:0007744|PDB:2PVV, ECO:0007744|PDB:2PVW, FT ECO:0007744|PDB:2XEF, ECO:0007744|PDB:2XEG, FT ECO:0007744|PDB:2XEI, ECO:0007744|PDB:2XEJ, FT ECO:0007744|PDB:3BHX, ECO:0007744|PDB:3BI0, FT ECO:0007744|PDB:3BI1, ECO:0007744|PDB:3BXM, FT ECO:0007744|PDB:3D7D, ECO:0007744|PDB:3D7F, FT ECO:0007744|PDB:3D7G, ECO:0007744|PDB:3D7H, FT ECO:0007744|PDB:3IWW, ECO:0007744|PDB:3RBU, FT ECO:0007744|PDB:3SJE, ECO:0007744|PDB:3SJF, FT ECO:0007744|PDB:3SJG, ECO:0007744|PDB:3SJX, FT ECO:0007744|PDB:4JYW, ECO:0007744|PDB:4JZ0, FT ECO:0007744|PDB:4LQG, ECO:0007744|PDB:4MCP, FT ECO:0007744|PDB:4MCQ, ECO:0007744|PDB:4MCR, FT ECO:0007744|PDB:4MCS, ECO:0007744|PDB:4NGM, FT ECO:0007744|PDB:4NGN, ECO:0007744|PDB:4NGP, FT ECO:0007744|PDB:4NGQ, ECO:0007744|PDB:4NGR, FT ECO:0007744|PDB:4NGS, ECO:0007744|PDB:4NGT, FT ECO:0007744|PDB:4OC0, ECO:0007744|PDB:4OC1, FT ECO:0007744|PDB:4OC2, ECO:0007744|PDB:4OC3, FT ECO:0007744|PDB:4OC4, ECO:0007744|PDB:4OC5, FT ECO:0007744|PDB:4OME, ECO:0007744|PDB:4P44, FT ECO:0007744|PDB:4P45, ECO:0007744|PDB:4P4B, FT ECO:0007744|PDB:4P4D, ECO:0007744|PDB:4P4E, FT ECO:0007744|PDB:4P4F, ECO:0007744|PDB:4P4I, FT ECO:0007744|PDB:4P4J" FT CARBOHYD 121 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:15152093, FT ECO:0000269|PubMed:16467855, ECO:0000269|PubMed:17372356, FT ECO:0000269|PubMed:17567119, ECO:0000269|PubMed:18234225, FT ECO:0000269|PubMed:19053759, ECO:0000269|PubMed:19301871, FT ECO:0007744|PDB:1Z8L, ECO:0007744|PDB:2C6C, FT ECO:0007744|PDB:2C6G, ECO:0007744|PDB:2CIJ, FT ECO:0007744|PDB:2JBJ, ECO:0007744|PDB:2JBK, FT ECO:0007744|PDB:2OOT, ECO:0007744|PDB:2OR4, FT ECO:0007744|PDB:2PVV, ECO:0007744|PDB:2PVW, FT ECO:0007744|PDB:2XEF, ECO:0007744|PDB:2XEG, FT ECO:0007744|PDB:2XEI, ECO:0007744|PDB:2XEJ, FT ECO:0007744|PDB:3BHX, ECO:0007744|PDB:3BI0, FT ECO:0007744|PDB:3BI1, ECO:0007744|PDB:3BXM, FT ECO:0007744|PDB:3D7D, ECO:0007744|PDB:3D7F, FT ECO:0007744|PDB:3D7G, ECO:0007744|PDB:3D7H, FT ECO:0007744|PDB:3IWW, ECO:0007744|PDB:3RBU, FT ECO:0007744|PDB:3SJE, ECO:0007744|PDB:3SJF, FT ECO:0007744|PDB:3SJG, ECO:0007744|PDB:3SJX, FT ECO:0007744|PDB:4JYW, ECO:0007744|PDB:4JZ0, FT ECO:0007744|PDB:4LQG, ECO:0007744|PDB:4MCP, FT ECO:0007744|PDB:4MCQ, ECO:0007744|PDB:4MCR, FT ECO:0007744|PDB:4MCS, ECO:0007744|PDB:4NGM, FT ECO:0007744|PDB:4NGN, ECO:0007744|PDB:4NGP, FT ECO:0007744|PDB:4NGQ, ECO:0007744|PDB:4NGR, FT ECO:0007744|PDB:4NGS, ECO:0007744|PDB:4NGT, FT ECO:0007744|PDB:4OC0, ECO:0007744|PDB:4OC1, FT ECO:0007744|PDB:4OC2, ECO:0007744|PDB:4OC3, FT ECO:0007744|PDB:4OC4, ECO:0007744|PDB:4OC5, FT ECO:0007744|PDB:4OME, ECO:0007744|PDB:4P44, FT ECO:0007744|PDB:4P45, ECO:0007744|PDB:4P4B, FT ECO:0007744|PDB:4P4D, ECO:0007744|PDB:4P4E, FT ECO:0007744|PDB:4P4F, ECO:0007744|PDB:4P4I, FT ECO:0007744|PDB:4P4J" FT CARBOHYD 140 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:15152093, FT ECO:0000269|PubMed:16467855, ECO:0000269|PubMed:17372356, FT ECO:0000269|PubMed:17567119, ECO:0000269|PubMed:18234225, FT ECO:0000269|PubMed:19053759, ECO:0000269|PubMed:19301871, FT ECO:0007744|PDB:1Z8L, ECO:0007744|PDB:2C6C, FT ECO:0007744|PDB:2C6G, ECO:0007744|PDB:2C6P, FT ECO:0007744|PDB:2CIJ, ECO:0007744|PDB:2JBJ, FT ECO:0007744|PDB:2JBK, ECO:0007744|PDB:2OOT, FT ECO:0007744|PDB:2OR4, ECO:0007744|PDB:2PVV, FT ECO:0007744|PDB:2PVW, ECO:0007744|PDB:2XEF, FT ECO:0007744|PDB:2XEG, ECO:0007744|PDB:2XEI, FT ECO:0007744|PDB:2XEJ, ECO:0007744|PDB:3BHX, FT ECO:0007744|PDB:3BI0, ECO:0007744|PDB:3BI1, FT ECO:0007744|PDB:3BXM, ECO:0007744|PDB:3D7D, FT ECO:0007744|PDB:3D7F, ECO:0007744|PDB:3D7G, FT ECO:0007744|PDB:3D7H, ECO:0007744|PDB:3IWW, FT ECO:0007744|PDB:3RBU, ECO:0007744|PDB:3SJE, FT ECO:0007744|PDB:3SJF, ECO:0007744|PDB:3SJG, FT ECO:0007744|PDB:4JYW, ECO:0007744|PDB:4JZ0, FT ECO:0007744|PDB:4LQG, ECO:0007744|PDB:4MCP, FT ECO:0007744|PDB:4MCQ, ECO:0007744|PDB:4MCR, FT ECO:0007744|PDB:4MCS, ECO:0007744|PDB:4NGM, FT ECO:0007744|PDB:4NGN, ECO:0007744|PDB:4NGP, FT ECO:0007744|PDB:4NGQ, ECO:0007744|PDB:4NGR, FT ECO:0007744|PDB:4NGS, ECO:0007744|PDB:4NGT, FT ECO:0007744|PDB:4OC0, ECO:0007744|PDB:4OC1, FT ECO:0007744|PDB:4OC2, ECO:0007744|PDB:4OC3, FT ECO:0007744|PDB:4OC4, ECO:0007744|PDB:4OC5, FT ECO:0007744|PDB:4OME, ECO:0007744|PDB:4P44, FT ECO:0007744|PDB:4P45, ECO:0007744|PDB:4P4B, FT ECO:0007744|PDB:4P4D, ECO:0007744|PDB:4P4E, FT ECO:0007744|PDB:4P4F, ECO:0007744|PDB:4P4I, FT ECO:0007744|PDB:4P4J" FT CARBOHYD 153 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:15152093, FT ECO:0007744|PDB:1Z8L" FT CARBOHYD 195 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:15152093, FT ECO:0000269|PubMed:16467855, ECO:0000269|PubMed:17372356, FT ECO:0000269|PubMed:17567119, ECO:0000269|PubMed:18234225, FT ECO:0000269|PubMed:19053759, ECO:0000269|PubMed:19301871, FT ECO:0007744|PDB:2C6C, ECO:0007744|PDB:2CIJ, FT ECO:0007744|PDB:2JBJ, ECO:0007744|PDB:2JBK, FT ECO:0007744|PDB:2OOT, ECO:0007744|PDB:2OR4, FT ECO:0007744|PDB:2PVV, ECO:0007744|PDB:2PVW, FT ECO:0007744|PDB:2XEF, ECO:0007744|PDB:2XEG, FT ECO:0007744|PDB:2XEI, ECO:0007744|PDB:2XEJ, FT ECO:0007744|PDB:3BHX, ECO:0007744|PDB:3BI0, FT ECO:0007744|PDB:3BI1, ECO:0007744|PDB:3BXM, FT ECO:0007744|PDB:3D7D, ECO:0007744|PDB:3D7F, FT ECO:0007744|PDB:3D7G, ECO:0007744|PDB:3D7H, FT ECO:0007744|PDB:3IWW, ECO:0007744|PDB:3RBU, FT ECO:0007744|PDB:3SJE, ECO:0007744|PDB:3SJF, FT ECO:0007744|PDB:3SJG, ECO:0007744|PDB:3SJX, FT ECO:0007744|PDB:4JYW, ECO:0007744|PDB:4JZ0, FT ECO:0007744|PDB:4LQG, ECO:0007744|PDB:4MCP, FT ECO:0007744|PDB:4MCQ, ECO:0007744|PDB:4MCR, FT ECO:0007744|PDB:4MCS, ECO:0007744|PDB:4NGM, FT ECO:0007744|PDB:4NGN, ECO:0007744|PDB:4NGP, FT ECO:0007744|PDB:4NGQ, ECO:0007744|PDB:4NGR, FT ECO:0007744|PDB:4NGS, ECO:0007744|PDB:4OC0, FT ECO:0007744|PDB:4OC1, ECO:0007744|PDB:4OC2, FT ECO:0007744|PDB:4OC3, ECO:0007744|PDB:4OC4, FT ECO:0007744|PDB:4OC5, ECO:0007744|PDB:4OME, FT ECO:0007744|PDB:4P44, ECO:0007744|PDB:4P45, FT ECO:0007744|PDB:4P4B, ECO:0007744|PDB:4P4D, FT ECO:0007744|PDB:4P4E, ECO:0007744|PDB:4P4F, FT ECO:0007744|PDB:4P4I, ECO:0007744|PDB:4P4J" FT CARBOHYD 336 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:12754519, FT ECO:0000269|PubMed:15152093" FT CARBOHYD 459 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:12754519, FT ECO:0000269|PubMed:15152093, ECO:0000269|PubMed:16467855, FT ECO:0000269|PubMed:17372356, ECO:0000269|PubMed:17567119, FT ECO:0000269|PubMed:18234225, ECO:0000269|PubMed:19053759, FT ECO:0000269|PubMed:19301871, ECO:0007744|PDB:1Z8L, FT ECO:0007744|PDB:2C6C, ECO:0007744|PDB:2C6G, FT ECO:0007744|PDB:2C6P, ECO:0007744|PDB:2CIJ, FT ECO:0007744|PDB:2JBJ, ECO:0007744|PDB:2JBK, FT ECO:0007744|PDB:2OOT, ECO:0007744|PDB:2OR4, FT ECO:0007744|PDB:2PVV, ECO:0007744|PDB:2PVW, FT ECO:0007744|PDB:2XEF, ECO:0007744|PDB:2XEG, FT ECO:0007744|PDB:2XEI, ECO:0007744|PDB:2XEJ, FT ECO:0007744|PDB:3BHX, ECO:0007744|PDB:3BI0, FT ECO:0007744|PDB:3BI1, ECO:0007744|PDB:3BXM, FT ECO:0007744|PDB:3D7D, ECO:0007744|PDB:3D7F, FT ECO:0007744|PDB:3D7G, ECO:0007744|PDB:3D7H, FT ECO:0007744|PDB:3IWW, ECO:0007744|PDB:3RBU, FT ECO:0007744|PDB:3SJE, ECO:0007744|PDB:3SJF, FT ECO:0007744|PDB:3SJG, ECO:0007744|PDB:3SJX, FT ECO:0007744|PDB:4JYW, ECO:0007744|PDB:4JZ0, FT ECO:0007744|PDB:4LQG, ECO:0007744|PDB:4MCP, FT ECO:0007744|PDB:4MCQ, ECO:0007744|PDB:4MCR, FT ECO:0007744|PDB:4MCS, ECO:0007744|PDB:4NGM, FT ECO:0007744|PDB:4NGN, ECO:0007744|PDB:4NGP, FT ECO:0007744|PDB:4NGQ, ECO:0007744|PDB:4NGR, FT ECO:0007744|PDB:4NGS, ECO:0007744|PDB:4NGT, FT ECO:0007744|PDB:4OC0, ECO:0007744|PDB:4OC1, FT ECO:0007744|PDB:4OC2, ECO:0007744|PDB:4OC3, FT ECO:0007744|PDB:4OC4, ECO:0007744|PDB:4OC5, FT ECO:0007744|PDB:4OME, ECO:0007744|PDB:4P44, FT ECO:0007744|PDB:4P45, ECO:0007744|PDB:4P4B, FT ECO:0007744|PDB:4P4D, ECO:0007744|PDB:4P4E, FT ECO:0007744|PDB:4P4F, ECO:0007744|PDB:4P4I, FT ECO:0007744|PDB:4P4J" FT CARBOHYD 476 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:12754519, FT ECO:0000269|PubMed:15152093, ECO:0000269|PubMed:16467855, FT ECO:0000269|PubMed:17372356, ECO:0000269|PubMed:17567119, FT ECO:0000269|PubMed:18234225, ECO:0000269|PubMed:19053759, FT ECO:0000269|PubMed:19301871, ECO:0007744|PDB:1Z8L, FT ECO:0007744|PDB:2C6C, ECO:0007744|PDB:2C6G, FT ECO:0007744|PDB:2C6P, ECO:0007744|PDB:2CIJ, FT ECO:0007744|PDB:2JBJ, ECO:0007744|PDB:2JBK, FT ECO:0007744|PDB:2OOT, ECO:0007744|PDB:2OR4, FT ECO:0007744|PDB:2PVV, ECO:0007744|PDB:2PVW, FT ECO:0007744|PDB:2XEF, ECO:0007744|PDB:2XEG, FT ECO:0007744|PDB:2XEI, ECO:0007744|PDB:2XEJ, FT ECO:0007744|PDB:3BHX, ECO:0007744|PDB:3BI0, FT ECO:0007744|PDB:3BI1, ECO:0007744|PDB:3BXM, FT ECO:0007744|PDB:3D7D, ECO:0007744|PDB:3D7F, FT ECO:0007744|PDB:3D7G, ECO:0007744|PDB:3D7H, FT ECO:0007744|PDB:3IWW, ECO:0007744|PDB:3RBU, FT ECO:0007744|PDB:3SJE, ECO:0007744|PDB:3SJF, FT ECO:0007744|PDB:3SJG, ECO:0007744|PDB:3SJX, FT ECO:0007744|PDB:4JYW, ECO:0007744|PDB:4JZ0, FT ECO:0007744|PDB:4LQG, ECO:0007744|PDB:4MCP, FT ECO:0007744|PDB:4MCQ, ECO:0007744|PDB:4MCR, FT ECO:0007744|PDB:4MCS, ECO:0007744|PDB:4NGM, FT ECO:0007744|PDB:4NGN, ECO:0007744|PDB:4NGP, FT ECO:0007744|PDB:4NGQ, ECO:0007744|PDB:4NGR, FT ECO:0007744|PDB:4NGS, ECO:0007744|PDB:4NGT, FT ECO:0007744|PDB:4OC0, ECO:0007744|PDB:4OC1, FT ECO:0007744|PDB:4OC2, ECO:0007744|PDB:4OC3, FT ECO:0007744|PDB:4OC4, ECO:0007744|PDB:4OC5, FT ECO:0007744|PDB:4OME, ECO:0007744|PDB:4P44, FT ECO:0007744|PDB:4P45, ECO:0007744|PDB:4P4B, FT ECO:0007744|PDB:4P4D, ECO:0007744|PDB:4P4E, FT ECO:0007744|PDB:4P4F, ECO:0007744|PDB:4P4I, FT ECO:0007744|PDB:4P4J" FT CARBOHYD 638 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:12754519, FT ECO:0000269|PubMed:15152093, ECO:0000269|PubMed:16467855, FT ECO:0000269|PubMed:17372356, ECO:0000269|PubMed:17567119, FT ECO:0000269|PubMed:18234225, ECO:0000269|PubMed:19053759, FT ECO:0000269|PubMed:19301871, ECO:0007744|PDB:1Z8L, FT ECO:0007744|PDB:2C6C, ECO:0007744|PDB:2C6G, FT ECO:0007744|PDB:2C6P, ECO:0007744|PDB:2CIJ, FT ECO:0007744|PDB:2JBJ, ECO:0007744|PDB:2JBK, FT ECO:0007744|PDB:2OOT, ECO:0007744|PDB:2OR4, FT ECO:0007744|PDB:2PVV, ECO:0007744|PDB:2PVW, FT ECO:0007744|PDB:2XEF, ECO:0007744|PDB:2XEG, FT ECO:0007744|PDB:2XEI, ECO:0007744|PDB:2XEJ, FT ECO:0007744|PDB:3BHX, ECO:0007744|PDB:3BI0, FT ECO:0007744|PDB:3BI1, ECO:0007744|PDB:3BXM, FT ECO:0007744|PDB:3D7D, ECO:0007744|PDB:3D7F, FT ECO:0007744|PDB:3D7G, ECO:0007744|PDB:3D7H, FT ECO:0007744|PDB:3IWW, ECO:0007744|PDB:3RBU, FT ECO:0007744|PDB:3SJE, ECO:0007744|PDB:3SJF, FT ECO:0007744|PDB:3SJG, ECO:0007744|PDB:3SJX, FT ECO:0007744|PDB:4JYW, ECO:0007744|PDB:4JZ0, FT ECO:0007744|PDB:4LQG, ECO:0007744|PDB:4MCP, FT ECO:0007744|PDB:4MCQ, ECO:0007744|PDB:4MCR, FT ECO:0007744|PDB:4MCS, ECO:0007744|PDB:4NGM, FT ECO:0007744|PDB:4NGN, ECO:0007744|PDB:4NGP, FT ECO:0007744|PDB:4NGQ, ECO:0007744|PDB:4NGR, FT ECO:0007744|PDB:4NGS, ECO:0007744|PDB:4NGT, FT ECO:0007744|PDB:4OC0, ECO:0007744|PDB:4OC1, FT ECO:0007744|PDB:4OC2, ECO:0007744|PDB:4OC3, FT ECO:0007744|PDB:4OC4, ECO:0007744|PDB:4OC5, FT ECO:0007744|PDB:4OME, ECO:0007744|PDB:4P44, FT ECO:0007744|PDB:4P45, ECO:0007744|PDB:4P4B, FT ECO:0007744|PDB:4P4D, ECO:0007744|PDB:4P4E, FT ECO:0007744|PDB:4P4F, ECO:0007744|PDB:4P4I, FT ECO:0007744|PDB:4P4J" FT VAR_SEQ 1..308 FT /note="Missing (in isoform 10)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_044287" FT VAR_SEQ 1..57 FT /note="Missing (in isoform PSMA')" FT /evidence="ECO:0000303|PubMed:7882349" FT /id="VSP_005336" FT VAR_SEQ 1..39 FT /note="MWNLLHETDSAVATARRPRWLCAGALVLAGGFFLLGFLF -> MTAGSSYPL FT FLAAYACTGCLAERL (in isoform PSMA-7 and isoform PSMA-9)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:17929272" FT /id="VSP_038058" FT VAR_SEQ 214..243 FT /note="VKNAQLAGAKGVILYSDPADYFAPGVKSYP -> NMLIGVELQRLLVFQVFL FT FIQLDTMMHRSS (in isoform PSMA-4)" FT /evidence="ECO:0000305" FT /id="VSP_040243" FT VAR_SEQ 244..750 FT /note="Missing (in isoform PSMA-4)" FT /evidence="ECO:0000305" FT /id="VSP_040244" FT VAR_SEQ 657..750 FT /note="NPIVLRMMNDQLMFLERAFIDPLGLPDRPFYRHVIYAPSSHNKYAGESFPGI FT YDALFDIESKVDPSKAWGEVKRQIYVAAFTVQAAAETLSEVA -> MSSMLQAATTSMQ FT GSHSQEFMMLCLILKAKWTLPRPGEK (in isoform PSMA-3)" FT /evidence="ECO:0000305" FT /id="VSP_040245" FT VAR_SEQ 657..688 FT /note="NPIVLRMMNDQLMFLERAFIDPLGLPDRPFYR -> K (in isoform FT PSMA-8 and isoform PSMA-9)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:17929272, ECO:0000303|Ref.10" FT /id="VSP_038059" FT VARIANT 23 FT /note="A -> T (in a colorectal cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036398" FT VARIANT 75 FT /note="Y -> H (in dbSNP:rs202676)" FT /evidence="ECO:0000269|PubMed:9838072" FT /id="VAR_024592" FT VARIANT 475 FT /note="H -> Y (correlates with lower folate and higher FT homocysteine levels; dbSNP:rs61886492)" FT /evidence="ECO:0000269|PubMed:11092759" FT /id="VAR_012736" FT VARIANT 627 FT /note="V -> L (in dbSNP:rs2988342)" FT /id="VAR_028882" FT MUTAGEN 51 FT /note="N->A: Loss of glycosylation. Reduces enzyme FT activity." FT /evidence="ECO:0000269|PubMed:15152093" FT MUTAGEN 76 FT /note="N->A: Loss of glycosylation. Reduces enzyme FT activity." FT /evidence="ECO:0000269|PubMed:15152093" FT MUTAGEN 121 FT /note="N->A: Loss of glycosylation. Severely reduced enzyme FT activity." FT /evidence="ECO:0000269|PubMed:15152093" FT MUTAGEN 140 FT /note="N->A: Loss of glycosylation. Severely reduced enzyme FT activity." FT /evidence="ECO:0000269|PubMed:15152093" FT MUTAGEN 153 FT /note="N->A: Loss of glycosylation. Severely reduced enzyme FT activity." FT /evidence="ECO:0000269|PubMed:15152093" FT MUTAGEN 195 FT /note="N->A: Loss of glycosylation. Severely reduced enzyme FT activity." FT /evidence="ECO:0000269|PubMed:15152093" FT MUTAGEN 336 FT /note="N->A: Loss of glycosylation. Reduces enzyme FT activity." FT /evidence="ECO:0000269|PubMed:15152093" FT MUTAGEN 377 FT /note="H->A,G,Q: Complete loss of activity." FT /evidence="ECO:0000269|PubMed:9882712" FT MUTAGEN 379 FT /note="D->E,N: Complete loss of activity." FT /evidence="ECO:0000269|PubMed:9882712" FT MUTAGEN 387 FT /note="D->E,L: Complete loss of activity." FT /evidence="ECO:0000269|PubMed:9882712" FT MUTAGEN 387 FT /note="D->N: No effect on enzyme activity." FT /evidence="ECO:0000269|PubMed:9882712" FT MUTAGEN 388 FT /note="P->A: No effect on enzyme activity." FT /evidence="ECO:0000269|PubMed:9882712" FT MUTAGEN 424 FT /note="E->A: Complete loss of activity." FT /evidence="ECO:0000269|PubMed:19301871" FT MUTAGEN 424 FT /note="E->D: Reduces enzyme activity." FT /evidence="ECO:0000269|PubMed:19301871" FT MUTAGEN 424 FT /note="E->Q: Reduces enzyme activity." FT /evidence="ECO:0000269|PubMed:19301871" FT MUTAGEN 425 FT /note="E->Q,D: Complete loss of activity." FT /evidence="ECO:0000269|PubMed:9882712" FT MUTAGEN 453 FT /note="D->N,L: Complete loss of activity." FT /evidence="ECO:0000269|PubMed:9882712" FT MUTAGEN 453 FT /note="D->Q: Reduces enzyme activity." FT /evidence="ECO:0000269|PubMed:9882712" FT MUTAGEN 454 FT /note="S->A: Reduces enzyme activity." FT /evidence="ECO:0000269|PubMed:9882712" FT MUTAGEN 459 FT /note="N->A: Loss of glycosylation. Reduces enzyme FT activity." FT /evidence="ECO:0000269|PubMed:15152093" FT MUTAGEN 476 FT /note="N->A: Loss of glycosylation. Reduces enzyme FT activity." FT /evidence="ECO:0000269|PubMed:15152093" FT MUTAGEN 638 FT /note="N->A: Loss of glycosylation. Abolishes enzyme FT activity." FT /evidence="ECO:0000269|PubMed:15152093" FT MUTAGEN 640 FT /note="T->A: Abolishes enzyme activity." FT /evidence="ECO:0000269|PubMed:15152093" FT CONFLICT 194 FT /note="I -> V (in Ref. 9; AAZ66619)" FT /evidence="ECO:0000305" FT CONFLICT 354 FT /note="R -> K (in Ref. 1; AA sequence)" FT /evidence="ECO:0000305" FT CONFLICT 398 FT /note="I -> N (in Ref. 8; ABO93402)" FT /evidence="ECO:0000305" FT HELIX 58..64 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 67..77 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 78..80 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 87..102 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 106..119 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 122..124 FT /evidence="ECO:0007829|PDB:2C6G" FT STRAND 127..131 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 137..140 FT /evidence="ECO:0007829|PDB:5O5T" FT TURN 149..151 FT /evidence="ECO:0007829|PDB:3D7H" FT HELIX 154..156 FT /evidence="ECO:0007829|PDB:3IWW" FT STRAND 174..176 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 182..190 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 200..204 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 210..219 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 223..228 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 231..234 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 244..247 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 269..272 FT /evidence="ECO:0007829|PDB:1Z8L" FT HELIX 283..285 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 294..297 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 299..306 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 317..319 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 322..325 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 330..333 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 335..337 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 341..346 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 349..362 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 365..377 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 381..383 FT /evidence="ECO:0007829|PDB:5O5T" FT TURN 385..388 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 389..407 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 413..422 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 424..426 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 429..437 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 439..445 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 446..451 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 455..457 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 459..466 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 468..470 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 471..479 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 480..482 FT /evidence="ECO:0007829|PDB:5O5T" FT TURN 486..490 FT /evidence="ECO:0007829|PDB:2JBK" FT HELIX 493..500 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 504..506 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 507..510 FT /evidence="ECO:0007829|PDB:4NGP" FT STRAND 517..519 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 521..525 FT /evidence="ECO:0007829|PDB:5O5T" FT TURN 526..528 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 531..538 FT /evidence="ECO:0007829|PDB:5O5T" FT TURN 541..543 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 546..548 FT /evidence="ECO:0007829|PDB:5O5T" FT TURN 550..553 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 559..565 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 571..589 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 597..615 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 619..625 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 630..652 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 658..673 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 684..686 FT /evidence="ECO:0007829|PDB:1Z8L" FT STRAND 689..695 FT /evidence="ECO:0007829|PDB:5O5T" FT STRAND 698..705 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 706..712 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 715..717 FT /evidence="ECO:0007829|PDB:5O5T" FT HELIX 721..744 FT /evidence="ECO:0007829|PDB:5O5T" SQ SEQUENCE 750 AA; 84331 MW; AD8C0A7DBF47901A CRC64; MWNLLHETDS AVATARRPRW LCAGALVLAG GFFLLGFLFG WFIKSSNEAT NITPKHNMKA FLDELKAENI KKFLYNFTQI PHLAGTEQNF QLAKQIQSQW KEFGLDSVEL AHYDVLLSYP NKTHPNYISI INEDGNEIFN TSLFEPPPPG YENVSDIVPP FSAFSPQGMP EGDLVYVNYA RTEDFFKLER DMKINCSGKI VIARYGKVFR GNKVKNAQLA GAKGVILYSD PADYFAPGVK SYPDGWNLPG GGVQRGNILN LNGAGDPLTP GYPANEYAYR RGIAEAVGLP SIPVHPIGYY DAQKLLEKMG GSAPPDSSWR GSLKVPYNVG PGFTGNFSTQ KVKMHIHSTN EVTRIYNVIG TLRGAVEPDR YVILGGHRDS WVFGGIDPQS GAAVVHEIVR SFGTLKKEGW RPRRTILFAS WDAEEFGLLG STEWAEENSR LLQERGVAYI NADSSIEGNY TLRVDCTPLM YSLVHNLTKE LKSPDEGFEG KSLYESWTKK SPSPEFSGMP RISKLGSGND FEVFFQRLGI ASGRARYTKN WETNKFSGYP LYHSVYETYE LVEKFYDPMF KYHLTVAQVR GGMVFELANS IVLPFDCRDY AVVLRKYADK IYSISMKHPQ EMKTYSVSFD SLFSAVKNFT EIASKFSERL QDFDKSNPIV LRMMNDQLMF LERAFIDPLG LPDRPFYRHV IYAPSSHNKY AGESFPGIYD ALFDIESKVD PSKAWGEVKR QIYVAAFTVQ AAAETLSEVA // ID GPC1_HUMAN Reviewed; 558 AA. AC P35052; B3KTD1; Q53QM4; DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot. DT 23-MAR-2010, sequence version 2. DT 28-JAN-2026, entry version 201. DE RecName: Full=Glypican-1; DE Contains: DE RecName: Full=Secreted glypican-1; DE Flags: Precursor; GN Name=GPC1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 24-53; 100-118 RP AND 298-317, GPI-ANCHOR AT SER-530, GLYCOSYLATION AT ASN-116, AND VARIANT RP GLY-500. RC TISSUE=Lung fibroblast; RX PubMed=2148568; DOI=10.1083/jcb.111.6.3165; RA David G., Lories V., Decock B., Marynen P., Cassiman J.-J., RA van den Berghe H.; RT "Molecular cloning of a phosphatidylinositol-anchored membrane heparan RT sulfate proteoglycan from human lung fibroblasts."; RL J. Cell Biol. 111:3165-3176(1990). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain, and Tongue; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT GLY-500. RC TISSUE=Salivary gland; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP COPPER-BINDING, S-NITROSYLATION, AND GLYCOSYLATION. RX PubMed=12732622; DOI=10.1074/jbc.m300394200; RA Mani K., Cheng F., Havsmark B., Jonsson M., Belting M., Fransson L.A.; RT "Prion, amyloid beta-derived Cu(II) ions, or free Zn(II) ions support S- RT nitroso-dependent autocleavage of glypican-1 heparan sulfate."; RL J. Biol. Chem. 278:38956-38965(2003). RN [7] RP SUBCELLULAR LOCATION, AND POSSIBLE ASSOCIATION WITH ALZHEIMER DISEASE. RX PubMed=15084524; DOI=10.1096/fj.03-1040fje; RA Watanabe N., Araki W., Chui D.H., Makifuchi T., Ihara Y., Tabira T.; RT "Glypican-1 as an Abeta binding HSPG in the human brain: its localization RT in DIG domains and possible roles in the pathogenesis of Alzheimer's RT disease."; RL FASEB J. 18:1013-1015(2004). RN [8] RP S-NITROSYLATION, AND ASSOCIATION WITH NIEMANN-PICK TYPE C1 DISEASE. RX PubMed=16645004; DOI=10.1093/glycob/cwj121; RA Mani K., Cheng F., Fransson L.A.; RT "Defective nitric oxide-dependent, deaminative cleavage of glypican-1 RT heparan sulfate in Niemann-Pick C1 fibroblasts."; RL Glycobiology 16:711-718(2006). RN [9] RP SUBCELLULAR LOCATION, S-NITROSYLATION, AND GLYCOSYLATION. RX PubMed=16971378; DOI=10.1093/glycob/cwl045; RA Mani K., Cheng F., Fransson L.A.; RT "Constitutive and vitamin C-induced, NO-catalyzed release of heparan RT sulfate from recycling glypican-1 in late endosomes."; RL Glycobiology 16:1251-1261(2006). RN [10] RP GLYCOSYLATION, AND LACK OF GLYCOSYLATION AT SER-55. RX PubMed=19775117; DOI=10.1021/bi901402x; RA Svensson G., Linse S., Mani K.; RT "Chemical and thermal unfolding of glypican-1: protective effect of heparan RT sulfate against heat-induced irreversible aggregation."; RL Biochemistry 48:9994-10004(2009). RN [11] RP S-NITROSYLATION, SUBCELLULAR LOCATION, AND GLYCOSYLATION. RX PubMed=19479373; DOI=10.1007/s10719-009-9243-z; RA Svensson G., Mani K.; RT "S-Nitrosylation of secreted recombinant human glypican-1."; RL Glycoconj. J. 26:1247-1257(2009). RN [12] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=19936054; DOI=10.1371/journal.ppat.1000666; RA Taylor D.R., Whitehouse I.J., Hooper N.M.; RT "Glypican-1 mediates both prion protein lipid raft association and disease RT isoform formation."; RL PLoS Pathog. 5:E1000666-E1000666(2009). RN [13] RP GLYCOSYLATION AT ASN-79 AND ASN-116, AND MUTAGENESIS OF ASN-79 AND ASN-116. RX PubMed=21932778; DOI=10.1021/bi200218s; RA Svensson G., Hyrenius Wittsten A., Linse S., Mani K.; RT "The structural role of N-linked glycans on human glypican-1."; RL Biochemistry 50:9377-9387(2011). RN [14] RP S-NITROSYLATION, GLYCOSYLATION, AND FUNCTION. RX PubMed=21642435; DOI=10.1074/jbc.m111.243345; RA Cheng F., Cappai R., Ciccotosto G.D., Svensson G., Multhaup G., RA Fransson L.A., Mani K.; RT "Suppression of amyloid beta A11 antibody immunoreactivity by vitamin C: RT possible role of heparan sulfate oligosaccharides derived from glypican-1 RT by ascorbate-induced, nitric oxide (NO)-catalyzed degradation."; RL J. Biol. Chem. 286:27559-27572(2011). RN [15] RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS), DISULFIDE BONDS, LACK OF RP GLYCOSYLATION AT SER-55, AND GLYCOSYLATION AT ASN-79 AND ASN-116. RX PubMed=22351761; DOI=10.1074/jbc.m111.322487; RA Svensson G., Awad W., Hakansson M., Mani K., Logan D.T.; RT "Crystal structure of N-glycosylated human glypican-1 core protein: RT Structure of two loops evolutionarily conserved in vertebrate glypican-1."; RL J. Biol. Chem. 287:14040-14051(2012). RN [16] RP VARIANT [LARGE SCALE ANALYSIS] ASP-337. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). CC -!- FUNCTION: Cell surface proteoglycan that bears heparan sulfate. Binds, CC via the heparan sulfate side chains, alpha-4 (V) collagen and CC participates in Schwann cell myelination (By similarity). May act as a CC catalyst in increasing the rate of conversion of prion protein PRPN(C) CC to PRNP(Sc) via associating (via the heparan sulfate side chains) with CC both forms of PRPN, targeting them to lipid rafts and facilitating CC their interaction. Required for proper skeletal muscle differentiation CC by sequestering FGF2 in lipid rafts preventing its binding to receptors CC (FGFRs) and inhibiting the FGF-mediated signaling. {ECO:0000250, CC ECO:0000269|PubMed:19936054, ECO:0000269|PubMed:21642435}. CC -!- INTERACTION: CC P35052; Q6PRD1: GPR179; NbExp=2; IntAct=EBI-8307554, EBI-20895185; CC P35052; Q8C419: Gpr158; Xeno; NbExp=3; IntAct=EBI-8307554, EBI-776313; CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor, GPI-anchor; CC Extracellular side. Endosome. Note=S-nitrosylated form recycled in CC endosomes. Localizes to CAV1-containing vesicles close to the cell CC surface. Cleavage of heparan sulfate side chains takes place mainly in CC late endosomes. Associates with both forms of PRNP in lipid rafts. CC Colocalizes with APP in perinuclear compartments and with CP in CC intracellular compartments. Associates with fibrillar APP amyloid-beta CC peptides in lipid rafts in Alzheimer disease brains. CC -!- SUBCELLULAR LOCATION: [Secreted glypican-1]: Secreted, extracellular CC space. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P35052-1; Sequence=Displayed; CC Name=2; CC IsoId=P35052-2; Sequence=VSP_055225, VSP_055226, VSP_055227; CC -!- PTM: S-nitrosylated in a Cu(2+)-dependent manner. Nitric acid (NO) is CC released from the nitrosylated cysteines by ascorbate or by some other CC reducing agent, in a Cu(2+) or Zn(2+) dependent manner. This free CC nitric oxide is then capable of cleaving the heparan sulfate side CC chains. CC -!- PTM: N- and O-glycosylated. N-glycosylation is mainly of the complex CC type containing sialic acid. O-glycosylated with heparan sulfate. The CC heparan sulfate chains can be cleaved either by the action of CC heparanase or, degraded by a deaminative process that uses nitric oxide CC (NO) released from the S-nitrosylated cysteines. This process is CC triggered by ascorbate, or by some other reducing agent, in a CC Cu(2+)- or Zn(2+) dependent manner. Cu(2+) ions are provided by CC ceruloproteins such as APP, PRNP or CP which associate with GCP1 in CC intracellular compartments or lipid rafts. CC {ECO:0000269|PubMed:12732622, ECO:0000269|PubMed:16971378, CC ECO:0000269|PubMed:19479373, ECO:0000269|PubMed:19775117, CC ECO:0000269|PubMed:2148568, ECO:0000269|PubMed:21642435, CC ECO:0000269|PubMed:21932778, ECO:0000269|PubMed:22351761}. CC -!- PTM: This cell-associated glypican is further processed to give rise to CC a medium-released species. CC -!- DISEASE: Note=Associates (via the heparan sulfate side chains) with CC fibrillar APP amyloid-beta peptides in primitive and classic amyloid CC plaques and may be involved in the deposition of these senile plaques CC in the Alzheimer disease (AD) brain (PubMed:15084524). CC {ECO:0000269|PubMed:15084524}. CC -!- DISEASE: Note=Misprocessing of GPC1 is found in fibroblasts of patients CC with Niemann-Pick Type C1 disease. This is due to the defective CC deaminative degradation of heparan sulfate chains (PubMed:16645004). CC {ECO:0000269|PubMed:16645004}. CC -!- SIMILARITY: Belongs to the glypican family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X54232; CAA38139.1; -; mRNA. DR EMBL; AK095397; BAG53043.1; -; mRNA. DR EMBL; AK096638; BAG53345.1; -; mRNA. DR EMBL; AC110619; AAY24160.1; -; Genomic_DNA. DR EMBL; CH471063; EAW71180.1; -; Genomic_DNA. DR EMBL; CH471063; EAW71183.1; -; Genomic_DNA. DR EMBL; BC051279; AAH51279.1; -; mRNA. DR CCDS; CCDS2534.1; -. [P35052-1] DR PIR; A36347; A36347. DR RefSeq; NP_002072.2; NM_002081.3. [P35052-1] DR PDB; 4ACR; X-ray; 2.55 A; A/B/C/D=24-479. DR PDB; 4AD7; X-ray; 2.94 A; A/B/C/D=24-529. DR PDB; 4BWE; X-ray; 2.46 A; A/B/C/D=24-479. DR PDB; 4YWT; X-ray; 2.38 A; A/B/C/D=24-527. DR PDBsum; 4ACR; -. DR PDBsum; 4AD7; -. DR PDBsum; 4BWE; -. DR PDBsum; 4YWT; -. DR AlphaFoldDB; P35052; -. DR SMR; P35052; -. DR BioGRID; 109079; 199. DR FunCoup; P35052; 649. DR IntAct; P35052; 335. DR MINT; P35052; -. DR STRING; 9606.ENSP00000264039; -. DR GlyConnect; 1279; 2 N-Linked glycans (1 site). DR GlyCosmos; P35052; 6 sites, 3 glycans. DR GlyGen; P35052; 13 sites, 15 N-linked glycans (2 sites), 3 O-linked glycans (7 sites). DR iPTMnet; P35052; -. DR PhosphoSitePlus; P35052; -. DR SwissPalm; P35052; -. DR BioMuta; GPC1; -. DR DMDM; 292495012; -. DR jPOST; P35052; -. DR MassIVE; P35052; -. DR PaxDb; 9606-ENSP00000264039; -. DR PeptideAtlas; P35052; -. DR ProteomicsDB; 54976; -. [P35052-1] DR Pumba; P35052; -. DR Antibodypedia; 34516; 376 antibodies from 38 providers. DR DNASU; 2817; -. DR Ensembl; ENST00000264039.7; ENSP00000264039.2; ENSG00000063660.10. [P35052-1] DR GeneID; 2817; -. DR KEGG; hsa:2817; -. DR MANE-Select; ENST00000264039.7; ENSP00000264039.2; NM_002081.3; NP_002072.2. DR UCSC; uc002vyw.5; human. [P35052-1] DR AGR; HGNC:4449; -. DR ClinPGx; PA28830; -. DR CTD; 2817; -. DR DisGeNET; 2817; -. DR GeneCards; GPC1; -. DR HGNC; HGNC:4449; GPC1. DR HPA; ENSG00000063660; Tissue enhanced (skin). DR MIM; 600395; gene. DR OpenTargets; ENSG00000063660; -. DR VEuPathDB; HostDB:ENSG00000063660; -. DR eggNOG; KOG3821; Eukaryota. DR GeneTree; ENSGT01050000244897; -. DR HOGENOM; CLU_024658_2_0_1; -. DR InParanoid; P35052; -. DR OMA; CNSYCRN; -. DR OrthoDB; 10010764at2759; -. DR PAN-GO; P35052; 6 GO annotations based on evolutionary models. DR PhylomeDB; P35052; -. DR PathwayCommons; P35052; -. DR Reactome; R-HSA-1971475; Glycosaminoglycan-protein linkage region biosynthesis. DR Reactome; R-HSA-2022928; HS-GAG biosynthesis. DR Reactome; R-HSA-2024096; HS-GAG degradation. DR Reactome; R-HSA-202733; Cell surface interactions at the vascular wall. DR Reactome; R-HSA-3560783; Defective B4GALT7 causes EDS, progeroid type. DR Reactome; R-HSA-3560801; Defective B3GAT3 causes JDSSDHD. DR Reactome; R-HSA-3656237; Defective EXT2 causes exostoses 2. DR Reactome; R-HSA-3656253; Defective EXT1 causes exostoses 1, TRPS2 and CHDS. DR Reactome; R-HSA-376176; Signaling by ROBO receptors. DR Reactome; R-HSA-4420332; Defective B3GALT6 causes EDSP2 and SEMDJL1. DR Reactome; R-HSA-9694614; Attachment and Entry. DR Reactome; R-HSA-975634; Retinoid metabolism and transport. DR Reactome; R-HSA-9820960; Respiratory syncytial virus (RSV) attachment and entry. DR Reactome; R-HSA-9833110; RSV-host interactions. DR SignaLink; P35052; -. DR SIGNOR; P35052; -. DR Agora; ENSG00000063660; -. DR BioGRID-ORCS; 2817; 14 hits in 1149 CRISPR screens. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; GPC1; human. DR EvolutionaryTrace; P35052; -. DR GeneWiki; Glypican_1; -. DR GenomeRNAi; 2817; -. DR Pharos; P35052; Tbio. DR PRO; PR:P35052; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; P35052; protein. DR Bgee; ENSG00000063660; Expressed in ventricular zone and 196 other cell types or tissues. DR ExpressionAtlas; P35052; baseline and differential. DR GO; GO:0009986; C:cell surface; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005768; C:endosome; IEA:UniProtKB-SubCell. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0031012; C:extracellular matrix; HDA:BHF-UCL. DR GO; GO:0005576; C:extracellular region; HDA:BHF-UCL. DR GO; GO:0005615; C:extracellular space; TAS:ProtInc. DR GO; GO:0005796; C:Golgi lumen; TAS:Reactome. DR GO; GO:0043202; C:lysosomal lumen; TAS:Reactome. DR GO; GO:0045121; C:membrane raft; ISS:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0098552; C:side of membrane; IEA:UniProtKB-KW. DR GO; GO:0045202; C:synapse; IBA:GO_Central. DR GO; GO:0005507; F:copper ion binding; IDA:UniProtKB. DR GO; GO:0017134; F:fibroblast growth factor binding; ISS:UniProtKB. DR GO; GO:0043236; F:laminin binding; ISS:UniProtKB. DR GO; GO:0016477; P:cell migration; IBA:GO_Central. DR GO; GO:0030200; P:heparan sulfate proteoglycan catabolic process; IDA:UniProtKB. DR GO; GO:0032288; P:myelin assembly; ISS:UniProtKB. DR GO; GO:0040037; P:negative regulation of fibroblast growth factor receptor signaling pathway; ISS:UniProtKB. DR GO; GO:2001016; P:positive regulation of skeletal muscle cell differentiation; ISS:UniProtKB. DR GO; GO:1905475; P:regulation of protein localization to membrane; IBA:GO_Central. DR GO; GO:0014037; P:Schwann cell differentiation; ISS:UniProtKB. DR DisProt; DP03324; -. DR InterPro; IPR001863; Glypican. DR InterPro; IPR019803; Glypican_CS. DR PANTHER; PTHR10822; GLYPICAN; 1. DR PANTHER; PTHR10822:SF8; GLYPICAN-1; 1. DR Pfam; PF01153; Glypican; 1. DR PROSITE; PS01207; GLYPICAN; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Copper; KW Direct protein sequencing; Disulfide bond; Endosome; Glycoprotein; KW GPI-anchor; Heparan sulfate; Lipoprotein; Membrane; Proteoglycan; KW Proteomics identification; Reference proteome; S-nitrosylation; Secreted; KW Signal; Zinc. FT SIGNAL 1..23 FT /evidence="ECO:0000269|PubMed:2148568" FT CHAIN 24..530 FT /note="Glypican-1" FT /id="PRO_0000012295" FT CHAIN 24..? FT /note="Secreted glypican-1" FT /id="PRO_0000333837" FT PROPEP 531..558 FT /note="Removed in mature form" FT /evidence="ECO:0000305" FT /id="PRO_0000012296" FT REGION 341..374 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 505..534 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 355..370 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT LIPID 530 FT /note="GPI-anchor amidated serine" FT /evidence="ECO:0000305|PubMed:2148568" FT CARBOHYD 79 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:21932778, FT ECO:0000269|PubMed:22351761" FT CARBOHYD 116 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:2148568, FT ECO:0000269|PubMed:21932778, ECO:0000269|PubMed:22351761" FT CARBOHYD 486 FT /note="O-linked (Xyl...) (heparan sulfate) serine" FT /evidence="ECO:0000305" FT CARBOHYD 488 FT /note="O-linked (Xyl...) (heparan sulfate) serine" FT /evidence="ECO:0000305" FT CARBOHYD 490 FT /note="O-linked (Xyl...) (heparan sulfate) serine" FT /evidence="ECO:0000305" FT DISULFID 32..68 FT /evidence="ECO:0000269|PubMed:22351761" FT DISULFID 62..256 FT /evidence="ECO:0000269|PubMed:22351761" FT DISULFID 69..259 FT /evidence="ECO:0000269|PubMed:22351761" FT DISULFID 191..343 FT /evidence="ECO:0000269|PubMed:22351761" FT DISULFID 246..279 FT /evidence="ECO:0000269|PubMed:22351761" FT DISULFID 268..415 FT /evidence="ECO:0000269|PubMed:22351761" FT DISULFID 272..401 FT /evidence="ECO:0000269|PubMed:22351761" FT VAR_SEQ 1..72 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_055225" FT VAR_SEQ 295..359 FT /note="DSMVLITDKFWGTSGVESVIGSVHTWLAEAINALQDNRDTLTAKVIQGCGNP FT KVNPQGPGPEEKR -> GEPPPARAAWNCLGECTTGGPGGRVVPSLELGPRDLIRDALT FT RARSGWCCRVEGPGCLLNVLSDV (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_055226" FT VAR_SEQ 360..558 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_055227" FT VARIANT 337 FT /note="A -> D (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036044" FT VARIANT 500 FT /note="S -> G (in dbSNP:rs2228331)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:2148568" FT /id="VAR_033977" FT MUTAGEN 79 FT /note="N->Q: Protein yield reduced by half. Protein yield FT reduced by 90%, abolishes N-glycosylation but no effect on FT secondary structure; when associated with Q-116." FT /evidence="ECO:0000269|PubMed:21932778" FT MUTAGEN 116 FT /note="N->Q: No effect on protein yield. Protein yield FT reduced by 90%, abolishes N-glycosylation but no effect on FT secondary structure; when associated with Q-79." FT /evidence="ECO:0000269|PubMed:21932778" FT HELIX 33..40 FT /evidence="ECO:0007829|PDB:4YWT" FT TURN 41..43 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 46..48 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 56..58 FT /evidence="ECO:0007829|PDB:4BWE" FT STRAND 60..62 FT /evidence="ECO:0007829|PDB:4YWT" FT STRAND 64..68 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 71..130 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 132..135 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 138..153 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 159..178 FT /evidence="ECO:0007829|PDB:4YWT" FT STRAND 180..182 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 187..192 FT /evidence="ECO:0007829|PDB:4YWT" FT TURN 201..204 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 205..237 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 244..254 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 256..259 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 269..279 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 281..284 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 287..300 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 301..304 FT /evidence="ECO:0007829|PDB:4YWT" FT STRAND 307..310 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 313..315 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 317..329 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 332..335 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 340..343 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 374..388 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 392..403 FT /evidence="ECO:0007829|PDB:4YWT" FT STRAND 418..422 FT /evidence="ECO:0007829|PDB:4YWT" FT STRAND 431..433 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 434..436 FT /evidence="ECO:0007829|PDB:4YWT" FT STRAND 440..442 FT /evidence="ECO:0007829|PDB:4YWT" FT HELIX 451..472 FT /evidence="ECO:0007829|PDB:4YWT" SQ SEQUENCE 558 AA; 61680 MW; 16553B56080A83C8 CRC64; MELRARGWWL LCAAAALVAC ARGDPASKSR SCGEVRQIYG AKGFSLSDVP QAEISGEHLR ICPQGYTCCT SEMEENLANR SHAELETALR DSSRVLQAML ATQLRSFDDH FQHLLNDSER TLQATFPGAF GELYTQNARA FRDLYSELRL YYRGANLHLE ETLAEFWARL LERLFKQLHP QLLLPDDYLD CLGKQAEALR PFGEAPRELR LRATRAFVAA RSFVQGLGVA SDVVRKVAQV PLGPECSRAV MKLVYCAHCL GVPGARPCPD YCRNVLKGCL ANQADLDAEW RNLLDSMVLI TDKFWGTSGV ESVIGSVHTW LAEAINALQD NRDTLTAKVI QGCGNPKVNP QGPGPEEKRR RGKLAPRERP PSGTLEKLVS EAKAQLRDVQ DFWISLPGTL CSEKMALSTA SDDRCWNGMA RGRYLPEVMG DGLANQINNP EVEVDITKPD MTIRQQIMQL KIMTNRLRSA YNGNDVDFQD ASDDGSGSGS GDGCLDDLCS RKVSRKSSSS RTPLTHALPG LSEQEGQKTS AASCPQPPTF LLPLLLFLAL TVARPRWR // ID GSK3B_HUMAN Reviewed; 420 AA. AC P49841; D3DN89; Q9BWH3; Q9UL47; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 02-MAY-2002, sequence version 2. DT 28-JAN-2026, entry version 273. DE RecName: Full=Glycogen synthase kinase-3 beta {ECO:0000305}; DE Short=GSK-3 beta; DE EC=2.7.11.26 {ECO:0000269|PubMed:14690523}; DE AltName: Full=Serine/threonine-protein kinase GSK3B; DE EC=2.7.11.1 {ECO:0000269|PubMed:17050006, ECO:0000269|PubMed:17681942, ECO:0000269|PubMed:21343617, ECO:0000269|PubMed:22539723, ECO:0000269|PubMed:25827072, ECO:0000269|PubMed:28992046, ECO:0000269|PubMed:29059170}; GN Name=GSK3B {ECO:0000312|HGNC:HGNC:4617}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND MUTAGENESIS OF SER-9. RX PubMed=7980435; DOI=10.1042/bj3030701; RA Stambolic V., Woodgett J.R.; RT "Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells RT via serine 9 phosphorylation."; RL Biochem. J. 303:701-704(1994). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Eye, and Placenta; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-28. RX PubMed=10486203; DOI=10.1006/geno.1999.5875; RA Lau K.F., Miller C.C.J., Anderton B.H., Shaw P.C.; RT "Molecular cloning and characterization of the human glycogen synthase RT kinase-3beta promoter."; RL Genomics 60:121-128(1999). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 185-202. RX PubMed=10523816; DOI=10.1038/sj.mp.4000538; RA Rhoads A.R., Karkera J.D., Detera-Wadleigh S.D.; RT "Radiation hybrid mapping of genes in the lithium-sensitive wnt signaling RT pathway."; RL Mol. Psychiatry 4:437-442(1999). RN [6] RP FUNCTION IN PHOSPHORYLATION OF JUN. RX PubMed=1846781; DOI=10.1016/0092-8674(91)90241-p; RA Boyle W.J., Smeal T., Defize L.H., Angel P., Woodgett J.R., Karin M., RA Hunter T.; RT "Activation of protein kinase C decreases phosphorylation of c-Jun at sites RT that negatively regulate its DNA-binding activity."; RL Cell 64:573-584(1991). RN [7] RP FUNCTION IN PHOSPHORYLATION OF EIF2BE/EIF2B5. RX PubMed=8397507; DOI=10.1042/bj2940625; RA Welsh G.I., Proud C.G.; RT "Glycogen synthase kinase-3 is rapidly inactivated in response to insulin RT and phosphorylates eukaryotic initiation factor eIF-2B."; RL Biochem. J. 294:625-629(1993). RN [8] RP PHOSPHORYLATION AT SER-9. RX PubMed=8250835; DOI=10.1042/bj2960015; RA Sutherland C., Leighton I.A., Cohen P.; RT "Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new RT kinase connections in insulin and growth-factor signalling."; RL Biochem. J. 296:15-19(1993). RN [9] RP ACTIVITY REGULATION BY AKT1. RX PubMed=8524413; DOI=10.1038/378785a0; RA Cross D.A., Alessi D.R., Cohen P., Andjelkovich M., Hemmings B.A.; RT "Inhibition of glycogen synthase kinase-3 by insulin mediated by protein RT kinase B."; RL Nature 378:785-789(1995). RN [10] RP FUNCTION IN PHOSPHORYLATION OF NFATC1/NFATC. RX PubMed=9072970; DOI=10.1126/science.275.5308.1930; RA Beals C.R., Sheridan C.M., Turck C.W., Gardner P., Crabtree G.R.; RT "Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3."; RL Science 275:1930-1934(1997). RN [11] RP INTERACTION WITH DNM1L. RC TISSUE=Liver; RX PubMed=9731200; DOI=10.1006/bbrc.1998.9253; RA Hong Y.-R., Chen C.-H., Cheng D.-S., Howng S.-L., Chow C.-C.; RT "Human dynamin-like protein interacts with the glycogen synthase kinase RT 3beta."; RL Biochem. Biophys. Res. Commun. 249:697-703(1998). RN [12] RP INTERACTION WITH MUC1, AND FUNCTION. RX PubMed=9819408; DOI=10.1128/mcb.18.12.7216; RA Li Y., Bharti A., Chen D., Gong J., Kufe D.; RT "Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma- RT associated antigen and beta-catenin."; RL Mol. Cell. Biol. 18:7216-7224(1998). RN [13] RP CHARACTERIZATION. RX PubMed=9736715; DOI=10.1073/pnas.95.19.11211; RA Delcommenne M., Tan C., Gray V., Rue L., Woodgett J.R., Dedhar S.; RT "Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase RT kinase 3 and protein kinase B/AKT by the integrin-linked kinase."; RL Proc. Natl. Acad. Sci. U.S.A. 95:11211-11216(1998). RN [14] RP INTERACTION WITH NIN. RX PubMed=11004522; DOI=10.1016/s0167-4781(00)00127-5; RA Hong Y.-R., Chen C.-H., Chang J.-H., Wang S.-K., Sy W.-D., Chou C.-K., RA Howng S.-L.; RT "Cloning and characterization of a novel human ninein protein that RT interacts with the glycogen synthase kinase 3beta."; RL Biochim. Biophys. Acta 1492:513-516(2000). RN [15] RP ASSOCIATION WITH DIABETES MELLITUS. RX PubMed=10868943; DOI=10.2337/diabetes.49.2.263; RA Nikoulina S.E., Ciaraldi T.P., Mudaliar S., Mohideen P., Carter L., RA Henry R.R.; RT "Potential role of glycogen synthase kinase-3 in skeletal muscle insulin RT resistance of type 2 diabetes."; RL Diabetes 49:263-271(2000). RN [16] RP FUNCTION, AND MUTAGENESIS OF ARG-96 AND LEU-128. RX PubMed=11430833; DOI=10.1016/s1097-2765(01)00253-2; RA Frame S., Cohen P., Biondi R.M.; RT "A common phosphate binding site explains the unique substrate specificity RT of GSK3 and its inactivation by phosphorylation."; RL Mol. Cell 7:1321-1327(2001). RN [17] RP PHOSPHORYLATION AT SER-9 BY SGK3, AND INTERACTION WITH SGK3. RX PubMed=12054501; DOI=10.1016/s0006-291x(02)00349-2; RA Dai F., Yu L., He H., Chen Y., Yu J., Yang Y., Xu Y., Ling W., Zhao S.; RT "Human serum and glucocorticoid-inducible kinase-like kinase (SGKL) RT phosphorylates glycogen syntheses kinase 3 beta (GSK-3beta) at serine-9 RT through direct interaction."; RL Biochem. Biophys. Res. Commun. 293:1191-1196(2002). RN [18] RP FUNCTION IN PHOSPHORYLATION OF MAPT/TAU. RX PubMed=14690523; DOI=10.1111/j.1471-4159.2004.02155.x; RA Cho J.H., Johnson G.V.; RT "Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3beta RT (GSK3beta) plays a critical role in regulating tau's ability to bind and RT stabilize microtubules."; RL J. Neurochem. 88:349-358(2004). RN [19] RP FUNCTION, INTERACTION WITH SNAI1, AND SUBCELLULAR LOCATION. RX PubMed=15448698; DOI=10.1038/ncb1173; RA Zhou B.P., Deng J., Xia W., Xu J., Li Y.M., Gunduz M., Hung M.C.; RT "Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control RT of epithelial-mesenchymal transition."; RL Nat. Cell Biol. 6:931-940(2004). RN [20] RP INTERACTION WITH CABYR. RX PubMed=15752768; DOI=10.1016/j.bbrc.2005.02.089; RA Hsu H.-C., Lee Y.-L., Cheng T.-S., Howng S.-L., Chang L.-K., Lu P.-J., RA Hong Y.-R.; RT "Characterization of two non-testis-specific CABYR variants that bind to RT GSK3beta with a proline-rich extensin-like domain."; RL Biochem. Biophys. Res. Commun. 329:1108-1117(2005). RN [21] RP FUNCTION, AND INTERACTION WITH SNAI1. RX PubMed=15647282; DOI=10.1074/jbc.m413878200; RA Yook J.I., Li X.Y., Ota I., Fearon E.R., Weiss S.J.; RT "Wnt-dependent regulation of the E-cadherin repressor snail."; RL J. Biol. Chem. 280:11740-11748(2005). RN [22] RP INTERACTION WITH GSKIP. RX PubMed=16981698; DOI=10.1021/bi061147r; RA Chou H.-Y., Howng S.-L., Cheng T.-S., Hsiao Y.-L., Lieu A.-S., Loh J.-K., RA Hwang S.-L., Lin C.-C., Hsu C.-M., Wang C., Lee C.-I., Lu P.-J., RA Chou C.-K., Huang C.-Y., Hong Y.-R.; RT "GSKIP is homologous to the axin GSK3beta interaction domain and functions RT as a negative regulator of GSK3beta."; RL Biochemistry 45:11379-11389(2006). RN [23] RP INTERACTION WITH PRUNE1. RX PubMed=16428445; DOI=10.1128/mcb.26.3.898-911.2006; RA Kobayashi T., Hino S., Oue N., Asahara T., Zollo M., Yasui W., Kikuchi A.; RT "Glycogen synthase kinase 3 and h-prune regulate cell migration by RT modulating focal adhesions."; RL Mol. Cell. Biol. 26:898-911(2006). RN [24] RP FUNCTION, AND PHOSPHORYLATION AT SER-9. RX PubMed=16484495; DOI=10.1126/science.1121613; RA Yin L., Wang J., Klein P.S., Lazar M.A.; RT "Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of RT the circadian clock."; RL Science 311:1002-1005(2006). RN [25] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF SER-9 AND 85-LYS-LYS-86. RX PubMed=17050006; DOI=10.1016/j.bbamcr.2006.09.015; RA Garcia-Alvarez G., Ventura V., Ros O., Aligue R., Gil J., Tauler A.; RT "Glycogen synthase kinase-3beta binds to E2F1 and regulates its RT transcriptional activity."; RL Biochim. Biophys. Acta 1773:375-382(2007). RN [26] RP INTERACTION WITH AXIN1. RX PubMed=17318175; DOI=10.1038/sj.emboj.7601607; RA Luo W., Peterson A., Garcia B.A., Coombs G., Kofahl B., Heinrich R., RA Shabanowitz J., Hunt D.F., Yost H.J., Virshup D.M.; RT "Protein phosphatase 1 regulates assembly and function of the beta-catenin RT degradation complex."; RL EMBO J. 26:1511-1521(2007). RN [27] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=17681942; DOI=10.1074/jbc.m703948200; RA Higgins M.J., Graves P.R., Graves L.M.; RT "Regulation of human cytidine triphosphate synthetase 1 by glycogen RT synthase kinase 3."; RL J. Biol. Chem. 282:29493-29503(2007). RN [28] RP FUNCTION, AND INTERACTION WITH BIRC2; DDX3X AND TNFRSF10B. RX PubMed=18846110; DOI=10.1038/cdd.2008.124; RA Sun M., Song L., Li Y., Zhou T., Jope R.S.; RT "Identification of an antiapoptotic protein complex at death receptors."; RL Cell Death Differ. 15:1887-1900(2008). RN [29] RP FUNCTION IN PHOSPHORYLATION OF SIK1. RX PubMed=18348280; DOI=10.1002/jcb.21737; RA Hashimoto Y.K., Satoh T., Okamoto M., Takemori H.; RT "Importance of autophosphorylation at Ser186 in the A-loop of salt RT inducible kinase 1 for its sustained kinase activity."; RL J. Cell. Biochem. 104:1724-1739(2008). RN [30] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-402, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [31] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-390, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [32] RP INTERACTION WITH MMP2. RX PubMed=19493954; DOI=10.1093/cvr/cvp175; RA Kandasamy A.D., Schulz R.; RT "Glycogen synthase kinase-3beta is activated by matrix metalloproteinase-2 RT mediated proteolysis in cardiomyoblasts."; RL Cardiovasc. Res. 83:698-706(2009). RN [33] RP FUNCTION, AND INTERACTION WITH CLOCK-BMAL1. RX PubMed=19946213; DOI=10.4161/cc.8.24.10273; RA Spengler M.L., Kuropatwinski K.K., Schumer M., Antoch M.P.; RT "A serine cluster mediates BMAL1-dependent CLOCK phosphorylation and RT degradation."; RL Cell Cycle 8:4138-4146(2009). RN [34] RP INTERACTION WITH CTNND2. RX PubMed=19706605; DOI=10.1074/jbc.m109.002659; RA Oh M., Kim H., Yang I., Park J.H., Cong W.T., Baek M.C., Bareiss S., Ki H., RA Lu Q., No J., Kwon I., Choi J.K., Kim K.; RT "GSK-3 phosphorylates delta-catenin and negatively regulates its stability RT via ubiquitination/proteosome-mediated proteolysis."; RL J. Biol. Chem. 284:28579-28589(2009). RN [35] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [36] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [37] RP FUNCTION, AND ALTERNATIVE SPLICING. RX PubMed=20067585; DOI=10.1111/j.1471-4159.2010.06581.x; RA Castano Z., Gordon-Weeks P.R., Kypta R.M.; RT "The neuron-specific isoform of glycogen synthase kinase-3beta is required RT for axon growth."; RL J. Neurochem. 113:117-130(2010). RN [38] RP FUNCTION. RX PubMed=20932480; DOI=10.1016/j.molcel.2010.09.013; RA Heyd F., Lynch K.W.; RT "Phosphorylation-dependent regulation of PSF by GSK3 controls CD45 RT alternative splicing."; RL Mol. Cell 40:126-137(2010). RN [39] RP INTERACTION WITH DAB2IP AND PPP2CA. RX PubMed=20080667; DOI=10.1073/pnas.0908133107; RA Xie D., Gore C., Liu J., Pong R.C., Mason R., Hao G., Long M., Kabbani W., RA Yu L., Zhang H., Chen H., Sun X., Boothman D.A., Min W., Hsieh J.T.; RT "Role of DAB2IP in modulating epithelial-to-mesenchymal transition and RT prostate cancer metastasis."; RL Proc. Natl. Acad. Sci. U.S.A. 107:2485-2490(2010). RN [40] RP FUNCTION, SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-9. RX PubMed=20937854; DOI=10.1073/pnas.1000975107; RA Zaoui K., Benseddik K., Daou P., Salaun D., Badache A.; RT "ErbB2 receptor controls microtubule capture by recruiting ACF7 to the RT plasma membrane of migrating cells."; RL Proc. Natl. Acad. Sci. U.S.A. 107:18517-18522(2010). RN [41] RP REVIEW ON FUNCTION, AND ACTIVITY REGULATION. RX PubMed=11749387; DOI=10.1021/cr000110o; RA Ali A., Hoeflich K.P., Woodgett J.R.; RT "Glycogen synthase kinase-3: properties, functions, and regulation."; RL Chem. Rev. 101:2527-2540(2001). RN [42] RP REVIEW ON FUNCTION. RX PubMed=17478001; DOI=10.1016/j.diabres.2007.01.033; RA Lee J., Kim M.S.; RT "The role of GSK3 in glucose homeostasis and the development of insulin RT resistance."; RL Diabetes Res. Clin. Pract. 77:S49-S57(2007). RN [43] RP REVIEW ON FUNCTION, AND ACTIVITY REGULATION. RX PubMed=19366350; DOI=10.1111/j.1476-5381.2008.00085.x; RA Rayasam G.V., Tulasi V.K., Sodhi R., Davis J.A., Ray A.; RT "Glycogen synthase kinase 3: more than a namesake."; RL Br. J. Pharmacol. 156:885-898(2009). RN [44] RP INTERACTION WITH GSKIP, AND COMPLEX FORMATION WITH PRKAR2A AND GSKIP. RX PubMed=20007971; DOI=10.1074/jbc.m109.047944; RA Hundsrucker C., Skroblin P., Christian F., Zenn H.M., Popara V., Joshi M., RA Eichhorst J., Wiesner B., Herberg F.W., Reif B., Rosenthal W., RA Klussmann E.; RT "Glycogen synthase kinase 3beta interaction protein functions as an A- RT kinase anchoring protein."; RL J. Biol. Chem. 285:5507-5521(2010). RN [45] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [46] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [47] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND PHOSPHORYLATION. RX PubMed=21029237; DOI=10.1111/j.1750-3639.2010.00437.x; RA Bose A., Mouton-Liger F., Paquet C., Mazot P., Vigny M., Gray F., Hugon J.; RT "Modulation of tau phosphorylation by the kinase PKR: implications in RT Alzheimer's disease."; RL Brain Pathol. 21:189-200(2011). RN [48] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=21343617; DOI=10.1126/scisignal.2001731; RA Chen C.H., Shaikenov T., Peterson T.R., Aimbetov R., Bissenbaev A.K., RA Lee S.W., Wu J., Lin H.K., Sarbassov D.D.; RT "ER stress inhibits mTORC2 and Akt signaling through GSK-3beta-mediated RT phosphorylation of rictor."; RL Sci. Signal. 4:ra10-ra10(2011). RN [49] RP FUNCTION. RX PubMed=22514281; DOI=10.1074/jbc.m111.306373; RA Sun L., Lv F., Guo X., Gao G.; RT "Glycogen synthase kinase 3? (GSK3?) modulates antiviral activity of zinc- RT finger antiviral protein (ZAP)."; RL J. Biol. Chem. 287:22882-22888(2012). RN [50] RP CATALYTIC ACTIVITY. RX PubMed=22539723; DOI=10.1126/science.1217032; RA Lin S.Y., Li T.Y., Liu Q., Zhang C., Li X., Chen Y., Zhang S.M., Lian G., RA Liu Q., Ruan K., Wang Z., Zhang C.S., Chien K.Y., Wu J., Li Q., Han J., RA Lin S.C.; RT "GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to RT autophagy."; RL Science 336:477-481(2012). RN [51] RP ADP-RIBOSYLATION BY PARP10. RX PubMed=23332125; DOI=10.1186/1478-811x-11-5; RA Feijs K.L., Kleine H., Braczynski A., Forst A.H., Herzog N., Verheugd P., RA Linzen U., Kremmer E., Luscher B.; RT "ARTD10 substrate identification on protein microarrays: regulation of RT GSK3beta by mono-ADP-ribosylation."; RL Cell Commun. Signal. 11:5-5(2013). RN [52] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-390, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [53] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [54] RP FUNCTION, INTERACTION WITH NCYM, AND PHOSPHORYLATION AT SER-9. RX PubMed=24391509; DOI=10.1371/journal.pgen.1003996; RA Suenaga Y., Islam S.M., Alagu J., Kaneko Y., Kato M., Tanaka Y., Kawana H., RA Hossain S., Matsumoto D., Yamamoto M., Shoji W., Itami M., Shibata T., RA Nakamura Y., Ohira M., Haraguchi S., Takatori A., Nakagawara A.; RT "NCYM, a Cis-antisense gene of MYCN, encodes a de novo evolved protein that RT inhibits GSK3beta resulting in the stabilization of MYCN in human RT neuroblastomas."; RL PLoS Genet. 10:E1003996-E1003996(2014). RN [55] RP PHOSPHORYLATION AT SER-9 AND TYR-216, INTERACTION WITH JPT1, AND RP SUBCELLULAR LOCATION. RX PubMed=25169422; DOI=10.1002/jcb.24956; RA Varisli L., Ozturk B.E., Akyuz G.K., Korkmaz K.S.; RT "HN1 negatively influences the beta-catenin/E-cadherin interaction, and RT contributes to migration in prostate cells."; RL J. Cell. Biochem. 116:170-178(2015). RN [56] RP INTERACTION WITH GSKIP, AND COMPLEX FORMATION WITH PRKAR2B AND GSKIP. RX PubMed=25920809; DOI=10.1016/j.bbamcr.2015.04.013; RA Loh J.K., Lin C.C., Yang M.C., Chou C.H., Chen W.S., Hong M.C., Cho C.L., RA Hsu C.M., Cheng J.T., Chou A.K., Chang C.H., Tseng C.N., Wang C.H., RA Lieu A.S., Howng S.L., Hong Y.R.; RT "GSKIP- and GSK3-mediated anchoring strengthens cAMP/PKA/Drp1 axis RT signaling in the regulation of mitochondrial elongation."; RL Biochim. Biophys. Acta 1853:1796-1807(2015). RN [57] RP FUNCTION, AND INTERACTION WITH RICTOR. RX PubMed=25897075; DOI=10.1074/jbc.m114.633057; RA Koo J., Wu X., Mao Z., Khuri F.R., Sun S.Y.; RT "Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7- RT mediated Ubiquitination and Proteasomal Degradation."; RL J. Biol. Chem. 290:14120-14129(2015). RN [58] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=25733715; DOI=10.1083/jcb.201406020; RA Albrecht L.V., Zhang L., Shabanowitz J., Purevjav E., Towbin J.A., RA Hunt D.F., Green K.J.; RT "GSK3- and PRMT-1-dependent modifications of desmoplakin control RT desmoplakin-cytoskeleton dynamics."; RL J. Cell Biol. 208:597-612(2015). RN [59] RP INTERACTION WITH GSKIP, AND COMPLEX FORMATION WITH PRKAR2A AND GSKIP. RX PubMed=27484798; DOI=10.1074/jbc.m116.738047; RA Dema A., Schroeter M.F., Perets E., Skroblin P., Moutty M.C., Deak V.A., RA Birchmeier W., Klussmann E.; RT "The A-Kinase Anchoring Protein (AKAP) Glycogen Synthase Kinase 3beta RT Interaction Protein (GSKIP) Regulates beta-Catenin through Its Interactions RT with Both Protein Kinase A (PKA) and GSK3beta."; RL J. Biol. Chem. 291:19618-19630(2016). RN [60] RP INTERACTION WITH AXIN1 AND GID8. RX PubMed=28829046; DOI=10.1038/cr.2017.107; RA Lu Y., Xie S., Zhang W., Zhang C., Gao C., Sun Q., Cai Y., Xu Z., Xiao M., RA Xu Y., Huang X., Wu X., Liu W., Wang F., Kang Y., Zhou T.; RT "Twa1/Gid8 is a beta-catenin nuclear retention factor in Wnt signaling and RT colorectal tumorigenesis."; RL Cell Res. 27:1422-1440(2017). RN [61] RP FUNCTION, AND INTERACTION WITH BMAL1. RX PubMed=28903391; DOI=10.18632/oncotarget.18973; RA Lu Y., Zheng X., Hu W., Bian S., Zhang Z., Tao D., Liu Y., Ma Y.; RT "Cancer/testis antigen PIWIL2 suppresses circadian rhythms by regulating RT the stability and activity of BMAL1 and CLOCK."; RL Oncotarget 8:54913-54924(2017). RN [62] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF SER-9. RX PubMed=28992046; DOI=10.1093/jmcb/mjx034; RA Wang D., Zhao J., Li S., Wei J., Nan L., Mallampalli R.K., RA Weathington N.M., Ma H., Zhao Y.; RT "Phosphorylated E2F1 is stabilized by nuclear USP11 to drive Peg10 gene RT expression and activate lung epithelial cells."; RL J. Mol. Cell Biol. 10:60-73(2018). RN [63] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=25827072; DOI=10.1016/j.canlet.2015.03.037; RA Jin Y., Shenoy A.K., Doernberg S., Chen H., Luo H., Shen H., Lin T., RA Tarrash M., Cai Q., Hu X., Fiske R., Chen T., Wu L., Mohammed K.A., RA Rottiers V., Lee S.S., Lu J.; RT "FBXO11 promotes ubiquitination of the Snail family of transcription RT factors in cancer progression and epidermal development."; RL Cancer Lett. 362:70-82(2015). RN [64] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=29059170; DOI=10.1038/onc.2017.370; RA Liu Y., Zhou H., Zhu R., Ding F., Li Y., Cao X., Liu Z.; RT "SPSB3 targets SNAIL for degradation in GSK-3beta phosphorylation-dependent RT manner and regulates metastasis."; RL Oncogene 37:768-776(2018). RN [65] RP FUNCTION. RX PubMed=30704899; DOI=10.1016/j.molcel.2018.12.017; RA Cheng X., Ma X., Zhu Q., Song D., Ding X., Li L., Jiang X., Wang X., RA Tian R., Su H., Shen Z., Chen S., Liu T., Gong W., Liu W., Sun Q.; RT "Pacer is a mediator of mTORC1 and GSK3-TIP60 signaling in regulation of RT autophagosome maturation and lipid metabolism."; RL Mol. Cell 73:1-15(2019). RN [66] RP INTERACTION WITH LMBR1L. RX PubMed=31073040; DOI=10.1126/science.aau0812; RA Choi J.H., Zhong X., McAlpine W., Liao T.C., Zhang D., Fang B., Russell J., RA Ludwig S., Nair-Gill E., Zhang Z., Wang K.W., Misawa T., Zhan X., Choi M., RA Wang T., Li X., Tang M., Sun Q., Yu L., Murray A.R., Moresco E.M.Y., RA Beutler B.; RT "LMBR1L regulates lymphopoiesis through Wnt/beta-catenin signaling."; RL Science 364:0-0(2019). RN [67] RP INTERACTION WITH PKP3. RX PubMed=34058472; DOI=10.1016/j.bbrc.2021.05.043; RA Hong J.Y., Zapata J., Blackburn A., Baumert R., Bae S.M., Ji H., Nam H.J., RA Miller R.K., McCrea P.D.; RT "A catenin of the plakophilin-subfamily, Pkp3, responds to canonical-Wnt RT pathway components and signals."; RL Biochem. Biophys. Res. Commun. 563:31-39(2021). RN [68] RP PHOSPHORYLATION AT SER-9, MUTAGENESIS OF CYS-14, SUBCELLULAR LOCATION, AND RP PALMITOYLATION AT CYS-14. RX PubMed=35606353; DOI=10.1038/s41389-022-00402-w; RA Zhao C., Yu H., Fan X., Niu W., Fan J., Sun S., Gong M., Zhao B., Fang Z., RA Chen X.; RT "GSK3beta palmitoylation mediated by ZDHHC4 promotes tumorigenicity of RT glioblastoma stem cells in temozolomide-resistant glioblastoma through the RT EZH2-STAT3 axis."; RL Oncogenesis 11:28-28(2022). RN [69] RP PHOSPHORYLATION AT SER-9. RX PubMed=34764205; DOI=10.1158/0008-5472.can-21-1020; RA Ren X., Rong Z., Liu X., Gao J., Xu X., Zi Y., Mu Y., Guan Y., Cao Z., RA Zhang Y., Zeng Z., Fan Q., Wang X., Pei Q., Wang X., Xin H., Li Z., Nie Y., RA Qiu Z., Li N., Sun L., Deng Y.; RT "The Protein Kinase Activity of NME7 Activates Wnt/beta-Catenin Signaling RT to Promote One-Carbon Metabolism in Hepatocellular Carcinoma."; RL Cancer Res. 82:60-74(2022). RN [70] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 35-386. RX PubMed=11440715; DOI=10.1016/s0092-8674(01)00374-9; RA Dajani R., Fraser E., Roe S.M., Young N., Good V., Dale T.C., Pearl L.H.; RT "Crystal structure of glycogen synthase kinase 3 beta: structural basis for RT phosphate-primed substrate specificity and autoinhibition."; RL Cell 105:721-732(2001). RN [71] RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 27-393 OF PHOSPHORYLATED GSK3B. RX PubMed=11738041; DOI=10.1016/s0969-2126(01)00679-7; RA Bax B., Carter P.S., Lewis C., Guy A.R., Bridges A., Tanner R., Pettman G., RA Mannix C., Culbert A.A., Brown M.J.B., Smith D.G., Reith A.D.; RT "The structure of phosphorylated GSK-3beta complexed with a peptide, RT FRATtide, that inhibits beta-catenin phosphorylation."; RL Structure 9:1143-1152(2001). RN [72] RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 35-384 IN COMPLEX WITH AXIN1, RP INTERACTION WITH AXIN1 AND FRAT1, FUNCTION, ACTIVITY REGULATION, AND RP PHOSPHORYLATION AT TYR-216. RX PubMed=12554650; DOI=10.1093/emboj/cdg068; RA Dajani R., Fraser E., Roe S.M., Yeo M., Good V.M., Thompson V., Dale T.C., RA Pearl L.H.; RT "Structural basis for recruitment of glycogen synthase kinase 3beta to the RT axin-APC scaffold complex."; RL EMBO J. 22:494-501(2003). CC -!- FUNCTION: Constitutively active protein kinase that acts as a negative CC regulator in the hormonal control of glucose homeostasis, Wnt signaling CC and regulation of transcription factors and microtubules, by CC phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), CC EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, CC NFATC1/NFATC, MAPT/TAU and MACF1 (PubMed:11430833, PubMed:12554650, CC PubMed:14690523, PubMed:16484495, PubMed:1846781, PubMed:20937854, CC PubMed:9072970). Requires primed phosphorylation of the majority of its CC substrates (PubMed:11430833, PubMed:16484495). In skeletal muscle, CC contributes to insulin regulation of glycogen synthesis by CC phosphorylating and inhibiting GYS1 activity and hence glycogen CC synthesis (PubMed:8397507). May also mediate the development of insulin CC resistance by regulating activation of transcription factors CC (PubMed:8397507). Regulates protein synthesis by controlling the CC activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as CC glycogen synthase (PubMed:8397507). In Wnt signaling, GSK3B forms a CC multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and CC phosphorylates the N-terminus of CTNNB1 leading to its degradation CC mediated by ubiquitin/proteasomes (PubMed:12554650). Phosphorylates JUN CC at sites proximal to its DNA-binding domain, thereby reducing its CC affinity for DNA (PubMed:1846781). Phosphorylates NFATC1/NFATC on CC conserved serine residues promoting NFATC1/NFATC nuclear export, CC shutting off NFATC1/NFATC gene regulation, and thereby opposing the CC action of calcineurin (PubMed:9072970). Phosphorylates MAPT/TAU on CC 'Thr-548', decreasing significantly MAPT/TAU ability to bind and CC stabilize microtubules (PubMed:14690523). MAPT/TAU is the principal CC component of neurofibrillary tangles in Alzheimer disease CC (PubMed:14690523). Plays an important role in ERBB2-dependent CC stabilization of microtubules at the cell cortex (PubMed:20937854). CC Phosphorylates MACF1, inhibiting its binding to microtubules which is CC critical for its role in bulge stem cell migration and skin wound CC repair (By similarity). Probably regulates NF-kappa-B (NFKB1) at the CC transcriptional level and is required for the NF-kappa-B-mediated anti- CC apoptotic response to TNF (TNF/TNFA) (By similarity). Negatively CC regulates replication in pancreatic beta-cells, resulting in apoptosis, CC loss of beta-cells and diabetes (By similarity). Through CC phosphorylation of the anti-apoptotic protein MCL1, may control cell CC apoptosis in response to growth factors deprivation (By similarity). CC Phosphorylates MUC1 in breast cancer cells, decreasing the interaction CC of MUC1 with CTNNB1/beta-catenin (PubMed:9819408). Is necessary for the CC establishment of neuronal polarity and axon outgrowth CC (PubMed:20067585). Phosphorylates MARK2, leading to inhibition of its CC activity (By similarity). Phosphorylates SIK1 at 'Thr-182', leading to CC sustainment of its activity (PubMed:18348280). Phosphorylates ZC3HAV1 CC which enhances its antiviral activity (PubMed:22514281). Phosphorylates CC SNAI1, leading to its ubiquitination and proteasomal degradation CC (PubMed:15448698, PubMed:15647282, PubMed:25827072, PubMed:29059170). CC Phosphorylates SFPQ at 'Thr-687' upon T-cell activation CC (PubMed:20932480). Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and CC stabilizes it by protecting it from proteasomal degradation. Regulates CC the circadian clock via phosphorylation of the major clock components CC including BMAL1, CLOCK and PER2 (PubMed:19946213, PubMed:28903391). CC Phosphorylates FBXL2 at 'Thr-404' and primes it for ubiquitination by CC the SCF(FBXO3) complex and proteasomal degradation (By similarity). CC Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal CC degradation (PubMed:19946213). Phosphorylates BMAL1 at 'Ser-17' and CC 'Ser-21' and primes it for ubiquitination and proteasomal degradation CC (PubMed:28903391). Phosphorylates OGT at 'Ser-3' or 'Ser-4' which CC positively regulates its activity. Phosphorylates MYCN in neuroblastoma CC cells which may promote its degradation (PubMed:24391509). Regulates CC the circadian rhythmicity of hippocampal long-term potentiation and CC BMAL1 and PER2 expression (By similarity). Acts as a regulator of CC autophagy by mediating phosphorylation of KAT5/TIP60 under starvation CC conditions, activating KAT5/TIP60 acetyltransferase activity and CC promoting acetylation of key autophagy regulators, such as ULK1 and CC RUBCNL/Pacer (PubMed:30704899). Negatively regulates extrinsic CC apoptotic signaling pathway via death domain receptors. Promotes the CC formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, CC at death receptors, including TNFRSF10B. The anti-apoptotic function is CC most effective with weak apoptotic signals and can be overcome by CC stronger stimulation (PubMed:18846110). Phosphorylates E2F1, promoting CC the interaction between E2F1 and USP11, stabilizing E2F1 and promoting CC its activity (PubMed:17050006, PubMed:28992046). Phosphorylates mTORC2 CC complex component RICTOR at 'Ser-1235' in response to endoplasmic CC stress, inhibiting mTORC2 (PubMed:21343617). Phosphorylates mTORC2 CC complex component RICTOR at 'Thr-1695' which facilitates FBXW7-mediated CC ubiquitination and subsequent degradation of RICTOR (PubMed:25897075). CC Phosphorylates FXR1, promoting FXR1 ubiquitination by the SCF(FBXO4) CC complex and FXR1 degradation by the proteasome (By similarity). CC Phosphorylates interleukin-22 receptor subunit IL22RA1, preventing its CC proteasomal degradation (By similarity). Phosphorylates and inhibits CC the CTP synthase and protein-asparagine deamidase activities of CTPS1 CC (PubMed:17681942). Phosphorylates DSP at multiple sequential serine CC residues in the C-terminus tail, promoting its recruitment to CC developing desmosome cell-cell junctions (PubMed:25733715). CC {ECO:0000250|UniProtKB:P18266, ECO:0000250|UniProtKB:Q9WV60, CC ECO:0000269|PubMed:11430833, ECO:0000269|PubMed:12554650, CC ECO:0000269|PubMed:14690523, ECO:0000269|PubMed:15448698, CC ECO:0000269|PubMed:15647282, ECO:0000269|PubMed:16484495, CC ECO:0000269|PubMed:17050006, ECO:0000269|PubMed:17681942, CC ECO:0000269|PubMed:18348280, ECO:0000269|PubMed:1846781, CC ECO:0000269|PubMed:18846110, ECO:0000269|PubMed:19946213, CC ECO:0000269|PubMed:20067585, ECO:0000269|PubMed:20932480, CC ECO:0000269|PubMed:20937854, ECO:0000269|PubMed:21343617, CC ECO:0000269|PubMed:22514281, ECO:0000269|PubMed:24391509, CC ECO:0000269|PubMed:25733715, ECO:0000269|PubMed:25827072, CC ECO:0000269|PubMed:25897075, ECO:0000269|PubMed:28903391, CC ECO:0000269|PubMed:28992046, ECO:0000269|PubMed:29059170, CC ECO:0000269|PubMed:30704899, ECO:0000269|PubMed:8397507, CC ECO:0000269|PubMed:9072970, ECO:0000269|PubMed:9819408}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein] CC + ADP + H(+); Xref=Rhea:RHEA:12801, Rhea:RHEA-COMP:13701, Rhea:RHEA- CC COMP:13702, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.26; CC Evidence={ECO:0000269|PubMed:14690523}; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-threonyl-[tau protein] + ATP = O-phospho-L-threonyl-[tau CC protein] + ADP + H(+); Xref=Rhea:RHEA:53904, Rhea:RHEA-COMP:13703, CC Rhea:RHEA-COMP:13704, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; CC EC=2.7.11.26; Evidence={ECO:0000269|PubMed:14690523}; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + CC H(+); Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:17050006, ECO:0000269|PubMed:17681942, CC ECO:0000269|PubMed:21343617, ECO:0000269|PubMed:22539723, CC ECO:0000269|PubMed:25827072, ECO:0000269|PubMed:28992046, CC ECO:0000269|PubMed:29059170}; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + CC ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA- CC COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:17050006}; CC -!- ACTIVITY REGULATION: Activated by phosphorylation at Tyr-216. In CC response to insulin, inhibited by phosphorylation at Ser-9 by PKB/AKT1 CC and RPS6KA3; phosphorylation at this site causes a conformational CC change, preventing access of substrates to the active site. Inhibited CC by IL22 treatment which also triggers phosphorylation at Ser-9, CC promoting inactivation (By similarity). Inhibited by lithium. CC {ECO:0000250|UniProtKB:Q9WV60, ECO:0000269|PubMed:11749387, CC ECO:0000269|PubMed:12554650, ECO:0000269|PubMed:19366350, CC ECO:0000269|PubMed:8524413}. CC -!- SUBUNIT: Monomer. Interacts with ARRB2, DISC1 and ZBED3 (By CC similarity). Interacts with CABYR, MMP2, MUC1, NIN and PRUNE1. CC Interacts with AXIN1; the interaction mediates hyperphosphorylation of CC CTNNB1 leading to its ubiquitination and destruction. Interacts with CC and phosphorylates SNAI1. Interacts with DNM1L (via a C-terminal CC domain). Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and CC GSK3B (By similarity). Interacts with SGK3. Interacts with DAB2IP (via CC C2 domain); the interaction stimulates GSK3B kinase activation. CC Interacts (via C2 domain) with PPP2CA. Interacts with the CLOCK-BMAL1 CC heterodimer (PubMed:19946213). Interacts with the BMAL1 CC (PubMed:28903391). Interacts with CTNND2 (PubMed:19706605). Interacts CC with NCYM (PubMed:24391509). The complex composed, at least, of APC, CC CTNNB1 and GSK3B interacts with JPT1; the interaction requires the CC inactive form of GSK3B (phosphorylated at 'Ser-9') (PubMed:25169422). CC Forms a complex composed of PRKAR2A or PRKAR2B, GSK3B and GSKIP through CC GSKIP interaction; facilitates PKA-induced phosphorylation and CC regulates GSK3B activity (PubMed:20007971, PubMed:25920809, CC PubMed:27484798). Interacts with GSKIP (PubMed:16981698). Interacts CC with GID8 (PubMed:28829046). Interacts with PIWIL2 (By similarity). CC Interacts with LMBR1L (PubMed:31073040). Interacts with DDX3X CC (PubMed:18846110). Interacts with BIRC2 (PubMed:18846110). Interacts CC with TNFRSF10B; TNFRSF10B stimulation inhibits GSK3B kinase activity CC (PubMed:18846110). Interacts with RICTOR; the interaction results in CC phosphorylation of RICTOR at 'Thr-1695' by GSK3B which facilitates CC FBXW7-mediated ubiquitination and subsequent degradation of RICTOR CC (PubMed:25897075). Found in a complex with SLC39A6, SLC39A10 and with CC GSK3B that controls NCAM1 phosphorylation (By similarity). Interacts CC with PKP3 (via ARM repeats); the interaction may be involved in PKP3 CC protein degradation (PubMed:34058472). {ECO:0000250|UniProtKB:P18266, CC ECO:0000250|UniProtKB:Q9WV60, ECO:0000269|PubMed:11004522, CC ECO:0000269|PubMed:12054501, ECO:0000269|PubMed:12554650, CC ECO:0000269|PubMed:15448698, ECO:0000269|PubMed:15647282, CC ECO:0000269|PubMed:15752768, ECO:0000269|PubMed:16428445, CC ECO:0000269|PubMed:16981698, ECO:0000269|PubMed:17318175, CC ECO:0000269|PubMed:18846110, ECO:0000269|PubMed:19493954, CC ECO:0000269|PubMed:19706605, ECO:0000269|PubMed:19946213, CC ECO:0000269|PubMed:20007971, ECO:0000269|PubMed:20080667, CC ECO:0000269|PubMed:24391509, ECO:0000269|PubMed:25169422, CC ECO:0000269|PubMed:25897075, ECO:0000269|PubMed:25920809, CC ECO:0000269|PubMed:27484798, ECO:0000269|PubMed:28829046, CC ECO:0000269|PubMed:28903391, ECO:0000269|PubMed:31073040, CC ECO:0000269|PubMed:34058472, ECO:0000269|PubMed:9731200, CC ECO:0000269|PubMed:9819408}. CC -!- INTERACTION: CC P49841; P31749: AKT1; NbExp=5; IntAct=EBI-373586, EBI-296087; CC P49841; P31751: AKT2; NbExp=2; IntAct=EBI-373586, EBI-296058; CC P49841; PRO_0000000093 [P05067]: APP; NbExp=2; IntAct=EBI-373586, EBI-2431589; CC P49841; O15169: AXIN1; NbExp=52; IntAct=EBI-373586, EBI-710484; CC P49841; Q9Y2T1: AXIN2; NbExp=6; IntAct=EBI-373586, EBI-4400025; CC P49841; Q96G01: BICD1; NbExp=7; IntAct=EBI-373586, EBI-1104509; CC P49841; O75952-3: CABYR; NbExp=3; IntAct=EBI-373586, EBI-10900795; CC P49841; O75952-5: CABYR; NbExp=3; IntAct=EBI-373586, EBI-10898671; CC P49841; P35222: CTNNB1; NbExp=20; IntAct=EBI-373586, EBI-491549; CC P49841; Q5VWQ8: DAB2IP; NbExp=2; IntAct=EBI-373586, EBI-2871881; CC P49841; Q5VWQ8-2: DAB2IP; NbExp=2; IntAct=EBI-373586, EBI-9543020; CC P49841; Q9NYF0: DACT1; NbExp=3; IntAct=EBI-373586, EBI-3951744; CC P49841; O75398: DEAF1; NbExp=2; IntAct=EBI-373586, EBI-718185; CC P49841; Q13144: EIF2B5; NbExp=2; IntAct=EBI-373586, EBI-4401110; CC P49841; Q92837: FRAT1; NbExp=5; IntAct=EBI-373586, EBI-3934879; CC P49841; Q9P0R6: GSKIP; NbExp=10; IntAct=EBI-373586, EBI-1052580; CC P49841; P13807: GYS1; NbExp=4; IntAct=EBI-373586, EBI-740553; CC P49841; O75581: LRP6; NbExp=4; IntAct=EBI-373586, EBI-910915; CC P49841; Q5S007: LRRK2; NbExp=7; IntAct=EBI-373586, EBI-5323863; CC P49841; P10636: MAPT; NbExp=4; IntAct=EBI-373586, EBI-366182; CC P49841; P10636-8: MAPT; NbExp=12; IntAct=EBI-373586, EBI-366233; CC P49841; Q14596: NBR1; NbExp=4; IntAct=EBI-373586, EBI-742698; CC P49841; Q8N4C6: NIN; NbExp=3; IntAct=EBI-373586, EBI-1164022; CC P49841; P17612: PRKACA; NbExp=7; IntAct=EBI-373586, EBI-476586; CC P49841; Q01201: RELB; NbExp=4; IntAct=EBI-373586, EBI-357837; CC P49841; Q13485: SMAD4; NbExp=5; IntAct=EBI-373586, EBI-347263; CC P49841; Q9NRG4: SMYD2; NbExp=2; IntAct=EBI-373586, EBI-1055671; CC P49841; O95863: SNAI1; NbExp=5; IntAct=EBI-373586, EBI-1045459; CC P49841; P37840: SNCA; NbExp=2; IntAct=EBI-373586, EBI-985879; CC P49841; Q6J9G0: STYK1; NbExp=2; IntAct=EBI-373586, EBI-6424915; CC P49841; P04637: TP53; NbExp=3; IntAct=EBI-373586, EBI-366083; CC P49841; Q14134: TRIM29; NbExp=2; IntAct=EBI-373586, EBI-702370; CC P49841; O95071: UBR5; NbExp=8; IntAct=EBI-373586, EBI-358329; CC P49841; P67809: YBX1; NbExp=2; IntAct=EBI-373586, EBI-354065; CC P49841; P16989: YBX3; NbExp=2; IntAct=EBI-373586, EBI-358193; CC P49841; P63104: YWHAZ; NbExp=4; IntAct=EBI-373586, EBI-347088; CC P49841; Q8IX07: ZFPM1; NbExp=2; IntAct=EBI-373586, EBI-3942619; CC P49841; O35625: Axin1; Xeno; NbExp=5; IntAct=EBI-373586, EBI-2365912; CC P49841; Q14DJ8: Axin1; Xeno; NbExp=2; IntAct=EBI-373586, EBI-4312125; CC P49841; Q02248: Ctnnb1; Xeno; NbExp=3; IntAct=EBI-373586, EBI-397872; CC P49841; Q811T9: Disc1; Xeno; NbExp=4; IntAct=EBI-373586, EBI-2298259; CC P49841; P63085: Mapk1; Xeno; NbExp=2; IntAct=EBI-373586, EBI-397697; CC P49841; P0DTC9: N; Xeno; NbExp=3; IntAct=EBI-373586, EBI-25475856; CC P49841-2; P05067: APP; NbExp=3; IntAct=EBI-15870655, EBI-77613; CC P49841-2; P35637: FUS; NbExp=3; IntAct=EBI-15870655, EBI-400434; CC P49841-2; P01106: MYC; NbExp=3; IntAct=EBI-15870655, EBI-447544; CC P49841-2; Q8BMD2-1: Dzip1; Xeno; NbExp=3; IntAct=EBI-15870655, EBI-16153101; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21029237, CC ECO:0000269|PubMed:25169422, ECO:0000269|PubMed:25733715, CC ECO:0000269|PubMed:35606353}. Nucleus {ECO:0000269|PubMed:15448698, CC ECO:0000269|PubMed:21029237}. Cell membrane CC {ECO:0000269|PubMed:20937854}. Note=The phosphorylated form shows CC localization to cytoplasm and cell membrane (PubMed:20937854). The CC MEMO1-RHOA-DIAPH1 signaling pathway controls localization of the CC phosphorylated form to the cell membrane (PubMed:20937854). CC {ECO:0000269|PubMed:20937854}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; Synonyms=GSK-3beta1; CC IsoId=P49841-1; Sequence=Displayed; CC Name=2; Synonyms=GSK-3beta2, neuron-specific; CC IsoId=P49841-2; Sequence=VSP_004790; CC -!- TISSUE SPECIFICITY: Expressed in testis, thymus, prostate and ovary and CC weakly expressed in lung, brain and kidney. Colocalizes with CC EIF2AK2/PKR and TAU in the Alzheimer disease (AD) brain. CC {ECO:0000269|PubMed:21029237}. CC -!- PTM: Phosphorylated by AKT1 and ILK1. Upon insulin-mediated signaling, CC the activated PKB/AKT1 protein kinase phosphorylates and deactivates CC GSK3B, resulting in the dephosphorylation and activation of GYS1. CC Activated by phosphorylation at Tyr-216 (PubMed:25169422). Inactivated CC by phosphorylation at Ser-9 (Probable). Phosphorylated in a circadian CC manner in the hippocampus (By similarity). CC {ECO:0000250|UniProtKB:Q9WV60, ECO:0000269|PubMed:12054501, CC ECO:0000269|PubMed:12554650, ECO:0000269|PubMed:16484495, CC ECO:0000269|PubMed:20937854, ECO:0000269|PubMed:21029237, CC ECO:0000269|PubMed:25169422, ECO:0000269|PubMed:8250835, CC ECO:0000305|PubMed:25169422}. CC -!- PTM: Mono-ADP-ribosylation by PARP10 negatively regulates kinase CC activity. {ECO:0000269|PubMed:23332125}. CC -!- PTM: Palmitoylated. Palmitoylation by ZDHHC4 prevents AKT1-mediated CC phosphorylation. {ECO:0000269|PubMed:35606353}. CC -!- MISCELLANEOUS: Higher expression and activity of GSK3B are found in the CC skeletal muscle (vastus lateralis) of patients with type 2 diabetes CC (PubMed:10868943). Several potent GSK3 (GSK3A and GSK3B) inhibitors CC have been identified and characterized in preclinical models for CC treatments of type 2 diabetes (PubMed:19366350). CC {ECO:0000305|PubMed:10868943, ECO:0000305|PubMed:19366350}. CC -!- MISCELLANEOUS: [Isoform 2]: May play a specific role in axon growth and CC neurite outgrowth. Reduced binding to AXIN1, reduced ability to CC phosphorylate MAPT/TAU. {ECO:0000269|PubMed:20067585}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr CC protein kinase family. GSK-3 subfamily. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/40761/GSK3B"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; L33801; AAA66475.1; -; mRNA. DR EMBL; CH471052; EAW79533.1; -; Genomic_DNA. DR EMBL; CH471052; EAW79536.1; -; Genomic_DNA. DR EMBL; BC000251; AAH00251.1; -; mRNA. DR EMBL; BC012760; AAH12760.1; -; mRNA. DR EMBL; AF074333; AAD48517.1; -; Genomic_DNA. DR EMBL; AF098789; AAC69340.1; -; Genomic_DNA. DR CCDS; CCDS2996.1; -. [P49841-2] DR CCDS; CCDS54628.1; -. [P49841-1] DR PIR; S53324; S53324. DR RefSeq; NP_001139628.1; NM_001146156.2. [P49841-1] DR RefSeq; NP_002084.2; NM_002093.3. [P49841-2] DR PDB; 1GNG; X-ray; 2.60 A; A/B=27-393. DR PDB; 1H8F; X-ray; 2.80 A; A/B=35-386. DR PDB; 1I09; X-ray; 2.70 A; A/B=1-420. DR PDB; 1J1B; X-ray; 1.80 A; A/B=1-420. DR PDB; 1J1C; X-ray; 2.10 A; A/B=1-420. DR PDB; 1O6K; X-ray; 1.70 A; C=3-12. DR PDB; 1O6L; X-ray; 1.60 A; C=3-12. DR PDB; 1O9U; X-ray; 2.40 A; A=35-384. DR PDB; 1PYX; X-ray; 2.40 A; A/B=1-420. DR PDB; 1Q3D; X-ray; 2.20 A; A/B=2-420. DR PDB; 1Q3W; X-ray; 2.30 A; A/B=2-420. DR PDB; 1Q41; X-ray; 2.10 A; A/B=2-420. DR PDB; 1Q4L; X-ray; 2.77 A; A/B=2-420. DR PDB; 1Q5K; X-ray; 1.94 A; A/B=7-420. DR PDB; 1R0E; X-ray; 2.25 A; A/B=35-420. DR PDB; 1UV5; X-ray; 2.80 A; A=35-384. DR PDB; 2JDO; X-ray; 1.80 A; C=3-12. DR PDB; 2JDR; X-ray; 2.30 A; C=3-12. DR PDB; 2JLD; X-ray; 2.35 A; A/B=1-420. DR PDB; 2O5K; X-ray; 3.20 A; A=29-393. DR PDB; 2OW3; X-ray; 2.80 A; A/B=35-386. DR PDB; 2UW9; X-ray; 2.10 A; C=3-12. DR PDB; 2X39; X-ray; 1.93 A; C=3-12. DR PDB; 2XH5; X-ray; 2.72 A; C=3-12. DR PDB; 3CQU; X-ray; 2.20 A; C=3-12. DR PDB; 3CQW; X-ray; 2.00 A; C=3-12. DR PDB; 3DU8; X-ray; 2.20 A; A/B=1-420. DR PDB; 3E87; X-ray; 2.30 A; C/D=3-12. DR PDB; 3E88; X-ray; 2.50 A; C/D=3-12. DR PDB; 3E8D; X-ray; 2.70 A; C/D=3-12. DR PDB; 3F7Z; X-ray; 2.40 A; A/B=35-383. DR PDB; 3F88; X-ray; 2.60 A; A/B=35-383. DR PDB; 3GB2; X-ray; 2.40 A; A=34-383. DR PDB; 3I4B; X-ray; 2.30 A; A/B=7-420. DR PDB; 3L1S; X-ray; 2.90 A; A/B=7-420. DR PDB; 3M1S; X-ray; 3.13 A; A/B=1-420. DR PDB; 3MV5; X-ray; 2.47 A; C=3-12. DR PDB; 3OW4; X-ray; 2.60 A; C/D=3-12. DR PDB; 3PUP; X-ray; 2.99 A; A/B=1-420. DR PDB; 3Q3B; X-ray; 2.70 A; A/B=2-420. DR PDB; 3QKK; X-ray; 2.30 A; C=3-12. DR PDB; 3QKL; X-ray; 1.90 A; C=3-12. DR PDB; 3SAY; X-ray; 2.23 A; A/B=1-420. DR PDB; 3SD0; X-ray; 2.70 A; A/B=35-384. DR PDB; 3ZDI; X-ray; 2.64 A; A=35-384. DR PDB; 3ZRK; X-ray; 2.37 A; A/B=23-393. DR PDB; 3ZRL; X-ray; 2.48 A; A/B=23-393. DR PDB; 3ZRM; X-ray; 2.49 A; A/B=23-393. DR PDB; 4ACC; X-ray; 2.21 A; A/B=1-420. DR PDB; 4ACD; X-ray; 2.60 A; A/B=1-420. DR PDB; 4ACG; X-ray; 2.60 A; A/B=1-420. DR PDB; 4ACH; X-ray; 2.60 A; A/B=1-420. DR PDB; 4AFJ; X-ray; 1.98 A; A/B=27-393. DR PDB; 4B7T; X-ray; 2.77 A; A=35-384. DR PDB; 4DIT; X-ray; 2.60 A; A=27-393. DR PDB; 4EKK; X-ray; 2.80 A; C/D=3-12. DR PDB; 4IQ6; X-ray; 3.12 A; A/B=1-420. DR PDB; 4J1R; X-ray; 2.70 A; A/B/C/D=1-420. DR PDB; 4J71; X-ray; 2.31 A; A/B=1-420. DR PDB; 4NM0; X-ray; 2.50 A; A=1-383. DR PDB; 4NM3; X-ray; 2.10 A; A=1-383. DR PDB; 4NM5; X-ray; 2.30 A; A=13-383. DR PDB; 4NM7; X-ray; 2.30 A; A=13-383. DR PDB; 4PTC; X-ray; 2.71 A; A/B=1-420. DR PDB; 4PTE; X-ray; 2.03 A; A/B=1-420. DR PDB; 4PTG; X-ray; 2.36 A; A/B=1-420. DR PDB; 5F94; X-ray; 2.51 A; A/B=36-385. DR PDB; 5F95; X-ray; 2.52 A; A/B=36-385. DR PDB; 5HLN; X-ray; 3.10 A; A/B=1-420. DR PDB; 5HLP; X-ray; 2.45 A; A/B=1-420. DR PDB; 5K5N; X-ray; 2.20 A; A/B=28-384. DR PDB; 5KPK; X-ray; 2.40 A; A/B=1-420. DR PDB; 5KPL; X-ray; 2.60 A; A/B=1-420. DR PDB; 5KPM; X-ray; 2.69 A; A/B=1-420. DR PDB; 5OY4; X-ray; 3.20 A; A/B=1-420. DR PDB; 5T31; X-ray; 2.85 A; A/B=1-420. DR PDB; 6B8J; X-ray; 2.60 A; A=1-420. DR PDB; 6BUU; X-ray; 2.40 A; F/G=3-12. DR PDB; 6GJO; X-ray; 2.91 A; A/B=7-420. DR PDB; 6GN1; X-ray; 2.60 A; A/B=27-393. DR PDB; 6H0U; X-ray; 2.30 A; A/B=1-420. DR PDB; 6HK3; X-ray; 2.35 A; A/B=35-384. DR PDB; 6HK4; X-ray; 2.50 A; A/B=35-384. DR PDB; 6HK7; X-ray; 3.20 A; A=36-382. DR PDB; 6NPZ; X-ray; 2.12 A; F/G=3-12. DR PDB; 6TCU; X-ray; 2.14 A; A=35-386. DR PDB; 6V6L; X-ray; 2.19 A; A=1-420. DR PDB; 6Y9R; X-ray; 2.08 A; A=35-384. DR PDB; 6Y9S; X-ray; 2.03 A; A/B=35-384. DR PDB; 7B6F; X-ray; 2.05 A; A=26-383. DR PDB; 7OY5; X-ray; 2.57 A; A/B=35-385. DR PDB; 7SXH; X-ray; 2.09 A; A=37-383. DR PDB; 7SXJ; X-ray; 1.85 A; A=34-383. DR PDB; 7U2Z; X-ray; 2.21 A; A/B=35-382. DR PDB; 7U31; X-ray; 2.38 A; A/B=36-385. DR PDB; 7U33; X-ray; 2.60 A; A/B=35-385. DR PDB; 7U36; X-ray; 2.75 A; A/B=35-385. DR PDB; 7Z1F; X-ray; 3.00 A; A/B=26-383. DR PDB; 7Z1G; X-ray; 2.85 A; A=26-383. DR PDB; 8AUZ; X-ray; 2.66 A; A/B=26-383. DR PDB; 8AV1; X-ray; 2.15 A; A/B=26-383. DR PDB; 8DJC; X-ray; 2.46 A; A/B=1-420. DR PDB; 8DJD; X-ray; 2.21 A; A/B=1-420. DR PDB; 8DJE; X-ray; 2.37 A; A/B=1-420. DR PDB; 8FF8; X-ray; 2.33 A; A/B=1-420. DR PDB; 8QJI; X-ray; 3.02 A; A=26-383. DR PDB; 8XN6; X-ray; 2.40 A; A/B=2-420. DR PDB; 9HUK; X-ray; 3.50 A; A/B=2-420. DR PDB; 9HUL; X-ray; 2.90 A; A/B=2-420. DR PDB; 9HV3; X-ray; 2.90 A; A/B=2-420. DR PDBsum; 1GNG; -. DR PDBsum; 1H8F; -. DR PDBsum; 1I09; -. DR PDBsum; 1J1B; -. DR PDBsum; 1J1C; -. DR PDBsum; 1O6K; -. DR PDBsum; 1O6L; -. DR PDBsum; 1O9U; -. DR PDBsum; 1PYX; -. DR PDBsum; 1Q3D; -. DR PDBsum; 1Q3W; -. DR PDBsum; 1Q41; -. DR PDBsum; 1Q4L; -. DR PDBsum; 1Q5K; -. DR PDBsum; 1R0E; -. DR PDBsum; 1UV5; -. DR PDBsum; 2JDO; -. DR PDBsum; 2JDR; -. DR PDBsum; 2JLD; -. DR PDBsum; 2O5K; -. DR PDBsum; 2OW3; -. DR PDBsum; 2UW9; -. DR PDBsum; 2X39; -. DR PDBsum; 2XH5; -. DR PDBsum; 3CQU; -. DR PDBsum; 3CQW; -. DR PDBsum; 3DU8; -. DR PDBsum; 3E87; -. DR PDBsum; 3E88; -. DR PDBsum; 3E8D; -. DR PDBsum; 3F7Z; -. DR PDBsum; 3F88; -. DR PDBsum; 3GB2; -. DR PDBsum; 3I4B; -. DR PDBsum; 3L1S; -. DR PDBsum; 3M1S; -. DR PDBsum; 3MV5; -. DR PDBsum; 3OW4; -. DR PDBsum; 3PUP; -. DR PDBsum; 3Q3B; -. DR PDBsum; 3QKK; -. DR PDBsum; 3QKL; -. DR PDBsum; 3SAY; -. DR PDBsum; 3SD0; -. DR PDBsum; 3ZDI; -. DR PDBsum; 3ZRK; -. DR PDBsum; 3ZRL; -. DR PDBsum; 3ZRM; -. DR PDBsum; 4ACC; -. DR PDBsum; 4ACD; -. DR PDBsum; 4ACG; -. DR PDBsum; 4ACH; -. DR PDBsum; 4AFJ; -. DR PDBsum; 4B7T; -. DR PDBsum; 4DIT; -. DR PDBsum; 4EKK; -. DR PDBsum; 4IQ6; -. DR PDBsum; 4J1R; -. DR PDBsum; 4J71; -. DR PDBsum; 4NM0; -. DR PDBsum; 4NM3; -. DR PDBsum; 4NM5; -. DR PDBsum; 4NM7; -. DR PDBsum; 4PTC; -. DR PDBsum; 4PTE; -. DR PDBsum; 4PTG; -. DR PDBsum; 5F94; -. DR PDBsum; 5F95; -. DR PDBsum; 5HLN; -. DR PDBsum; 5HLP; -. DR PDBsum; 5K5N; -. DR PDBsum; 5KPK; -. DR PDBsum; 5KPL; -. DR PDBsum; 5KPM; -. DR PDBsum; 5OY4; -. DR PDBsum; 5T31; -. DR PDBsum; 6B8J; -. DR PDBsum; 6BUU; -. DR PDBsum; 6GJO; -. DR PDBsum; 6GN1; -. DR PDBsum; 6H0U; -. DR PDBsum; 6HK3; -. DR PDBsum; 6HK4; -. DR PDBsum; 6HK7; -. DR PDBsum; 6NPZ; -. DR PDBsum; 6TCU; -. DR PDBsum; 6V6L; -. DR PDBsum; 6Y9R; -. DR PDBsum; 6Y9S; -. DR PDBsum; 7B6F; -. DR PDBsum; 7OY5; -. DR PDBsum; 7SXH; -. DR PDBsum; 7SXJ; -. DR PDBsum; 7U2Z; -. DR PDBsum; 7U31; -. DR PDBsum; 7U33; -. DR PDBsum; 7U36; -. DR PDBsum; 7Z1F; -. DR PDBsum; 7Z1G; -. DR PDBsum; 8AUZ; -. DR PDBsum; 8AV1; -. DR PDBsum; 8DJC; -. DR PDBsum; 8DJD; -. DR PDBsum; 8DJE; -. DR PDBsum; 8FF8; -. DR PDBsum; 8QJI; -. DR PDBsum; 8XN6; -. DR PDBsum; 9HUK; -. DR PDBsum; 9HUL; -. DR PDBsum; 9HV3; -. DR AlphaFoldDB; P49841; -. DR SMR; P49841; -. DR BioGRID; 109187; 867. DR ComplexPortal; CPX-109; Beta-catenin destruction core complex, APC-AXIN1-GSK3B variant. DR ComplexPortal; CPX-439; Beta-catenin destruction core complex, APC-AXIN2-GSK3B variant. DR ComplexPortal; CPX-440; Beta-catenin destruction core complex, APC2-AXIN2-GSK3B variant. DR ComplexPortal; CPX-459; Nuclear export complex FRAT1-GSK3B. DR ComplexPortal; CPX-462; Nuclear export complex FRAT2-GSK3B. DR ComplexPortal; CPX-99; Beta-catenin destruction core complex, APC2-AXIN1-GSK3B variant. DR CORUM; P49841; -. DR DIP; DIP-878N; -. DR ELM; P49841; -. DR FunCoup; P49841; 3788. DR IntAct; P49841; 399. DR MINT; P49841; -. DR STRING; 9606.ENSP00000324806; -. DR BindingDB; P49841; -. DR ChEMBL; CHEMBL262; -. DR DrugBank; DB08073; (2S)-1-(1H-INDOL-3-YL)-3-{[5-(3-METHYL-1H-INDAZOL-5-YL)PYRIDIN-3-YL]OXY}PROPAN-2-AMINE. DR DrugBank; DB07149; (7S)-2-(2-aminopyrimidin-4-yl)-7-(2-fluoroethyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. DR DrugBank; DB07014; 2-(1,3-benzodioxol-5-yl)-5-[(3-fluoro-4-methoxybenzyl)sulfanyl]-1,3,4-oxadiazole. DR DrugBank; DB07676; 3-({[(3S)-3,4-dihydroxybutyl]oxy}amino)-1H,2'H-2,3'-biindol-2'-one. DR DrugBank; DB01772; 3-[3-(2,3-Dihydroxy-Propylamino)-Phenyl]-4-(5-Fluoro-1-Methyl-1h-Indol-3-Yl)-Pyrrole-2,5-Dione. DR DrugBank; DB07859; 4-(4-CHLOROPHENYL)-4-[4-(1H-PYRAZOL-4-YL)PHENYL]PIPERIDINE. DR DrugBank; DB07585; 5-(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine. DR DrugBank; DB07058; 5-[1-(4-methoxyphenyl)-1H-benzimidazol-6-yl]-1,3,4-oxadiazole-2(3H)-thione. DR DrugBank; DB03444; 6-bromoindirubin-3'-oxime. DR DrugBank; DB04014; Alsterpaullone. DR DrugBank; DB01950; AR-AO-14418. DR DrugBank; DB03777; Bisindolylmaleimide I. DR DrugBank; DB12429; CI-1040. DR DrugBank; DB08846; Ellagic acid. DR DrugBank; DB16047; Elraglusib. DR DrugBank; DB12010; Fostamatinib. DR DrugBank; DB02052; Indirubin-3'-monoxime. DR DrugBank; DB07947; ISOQUINOLINE-5-SULFONIC ACID (2-(2-(4-CHLOROBENZYLOXY)ETHYLAMINO)ETHYL)AMIDE. DR DrugBank; DB14509; Lithium carbonate. DR DrugBank; DB01356; Lithium cation. DR DrugBank; DB14507; Lithium citrate. DR DrugBank; DB14508; Lithium succinate. DR DrugBank; DB11913; LY-2090314. DR DrugBank; DB08454; N-(5-METHYL-1H-PYRAZOL-3-YL)-2-PHENYLQUINAZOLIN-4-AMINE. DR DrugBank; DB07812; N-[(1S)-2-amino-1-phenylethyl]-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiophene-2-carboxamide. DR DrugBank; DB07584; N-[2-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine. DR DrugBank; DB07126; O6-CYCLOHEXYLMETHOXY-2-(4'-SULPHAMOYLANILINO) PURINE. DR DrugBank; DB04395; Phosphoaminophosphonic Acid-Adenylate Ester. DR DrugBank; DB01793; SB-409513. DR DrugBank; DB02010; Staurosporine. DR DrugBank; DB04462; Tetrabromo-2-Benzotriazole. DR DrugBank; DB12129; Tideglusib. DR DrugCentral; P49841; -. DR GuidetoPHARMACOLOGY; 2030; -. DR GlyCosmos; P49841; 3 sites, 1 glycan. DR GlyGen; P49841; 24 sites, 1 O-linked glycan (24 sites). DR iPTMnet; P49841; -. DR PhosphoSitePlus; P49841; -. DR SwissPalm; P49841; -. DR BioMuta; GSK3B; -. DR DMDM; 20455502; -. DR CPTAC; CPTAC-3038; -. DR CPTAC; CPTAC-3039; -. DR CPTAC; CPTAC-5749; -. DR CPTAC; CPTAC-5750; -. DR CPTAC; CPTAC-5751; -. DR CPTAC; CPTAC-5790; -. DR CPTAC; CPTAC-5791; -. DR CPTAC; CPTAC-804; -. DR CPTAC; non-CPTAC-5401; -. DR CPTAC; non-CPTAC-5403; -. DR CPTAC; non-CPTAC-5404; -. DR CPTAC; non-CPTAC-5554; -. DR CPTAC; non-CPTAC-5556; -. DR CPTAC; non-CPTAC-5705; -. DR jPOST; P49841; -. DR MassIVE; P49841; -. DR PaxDb; 9606-ENSP00000324806; -. DR PeptideAtlas; P49841; -. DR ProteomicsDB; 56151; -. [P49841-1] DR ProteomicsDB; 56152; -. [P49841-2] DR Pumba; P49841; -. DR Antibodypedia; 4266; 1367 antibodies from 55 providers. DR CPTC; P49841; 10 antibodies. DR DNASU; 2932; -. DR Ensembl; ENST00000264235.13; ENSP00000264235.9; ENSG00000082701.18. [P49841-1] DR Ensembl; ENST00000316626.6; ENSP00000324806.5; ENSG00000082701.18. [P49841-2] DR GeneID; 2932; -. DR KEGG; hsa:2932; -. DR MANE-Select; ENST00000264235.13; ENSP00000264235.9; NM_001146156.2; NP_001139628.1. DR UCSC; uc003edn.4; human. [P49841-1] DR AGR; HGNC:4617; -. DR ClinPGx; PA29009; -. DR CTD; 2932; -. DR DisGeNET; 2932; -. DR GeneCards; GSK3B; -. DR HGNC; HGNC:4617; GSK3B. DR HPA; ENSG00000082701; Low tissue specificity. DR MalaCards; GSK3B; -. DR MIM; 605004; gene. DR OpenTargets; ENSG00000082701; -. DR VEuPathDB; HostDB:ENSG00000082701; -. DR eggNOG; KOG0658; Eukaryota. DR GeneTree; ENSGT00520000055635; -. DR HOGENOM; CLU_000288_181_20_1; -. DR InParanoid; P49841; -. DR OMA; MKTTMPM; -. DR OrthoDB; 272141at2759; -. DR PAN-GO; P49841; 14 GO annotations based on evolutionary models. DR PhylomeDB; P49841; -. DR BRENDA; 2.7.11.26; 2681. DR PathwayCommons; P49841; -. DR Reactome; R-HSA-195253; Degradation of beta-catenin by the destruction complex. DR Reactome; R-HSA-196299; Beta-catenin phosphorylation cascade. DR Reactome; R-HSA-198323; AKT phosphorylates targets in the cytosol. DR Reactome; R-HSA-3371453; Regulation of HSF1-mediated heat shock response. DR Reactome; R-HSA-399956; CRMPs in Sema3A signaling. DR Reactome; R-HSA-4641262; Disassembly of the destruction complex and recruitment of AXIN to the membrane. DR Reactome; R-HSA-5250924; B-WICH complex positively regulates rRNA expression. DR Reactome; R-HSA-5339716; Signaling by GSK3beta mutants. DR Reactome; R-HSA-5358747; CTNNB1 S33 mutants aren't phosphorylated. DR Reactome; R-HSA-5358749; CTNNB1 S37 mutants aren't phosphorylated. DR Reactome; R-HSA-5358751; CTNNB1 S45 mutants aren't phosphorylated. DR Reactome; R-HSA-5358752; CTNNB1 T41 mutants aren't phosphorylated. DR Reactome; R-HSA-5467337; APC truncation mutants have impaired AXIN binding. DR Reactome; R-HSA-5467340; AXIN missense mutants destabilize the destruction complex. DR Reactome; R-HSA-5467348; Truncations of AMER1 destabilize the destruction complex. DR Reactome; R-HSA-5610783; Degradation of GLI2 by the proteasome. DR Reactome; R-HSA-5610785; GLI3 is processed to GLI3R by the proteasome. DR Reactome; R-HSA-5674400; Constitutive Signaling by AKT1 E17K in Cancer. DR Reactome; R-HSA-75815; Ubiquitin-dependent degradation of Cyclin D. DR Reactome; R-HSA-8939902; Regulation of RUNX2 expression and activity. DR Reactome; R-HSA-9683610; Maturation of nucleoprotein. DR Reactome; R-HSA-9694631; Maturation of nucleoprotein. DR Reactome; R-HSA-9762114; GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2. DR Reactome; R-HSA-9856649; Transcriptional and post-translational regulation of MITF-M expression and activity. DR SignaLink; P49841; -. DR SIGNOR; P49841; -. DR Agora; ENSG00000082701; -. DR BioGRID-ORCS; 2932; 75 hits in 1226 CRISPR screens. DR CD-CODE; 804901D1; Nuclear speckle. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; GSK3B; human. DR EvolutionaryTrace; P49841; -. DR GeneWiki; GSK3B; -. DR GenomeRNAi; 2932; -. DR Pharos; P49841; Tclin. DR PRO; PR:P49841; -. DR Proteomes; UP000005640; Chromosome 3. DR RNAct; P49841; protein. DR Bgee; ENSG00000082701; Expressed in calcaneal tendon and 197 other cell types or tissues. DR ExpressionAtlas; P49841; baseline and differential. DR GO; GO:0030424; C:axon; ISS:ARUK-UCL. DR GO; GO:0030877; C:beta-catenin destruction complex; IDA:UniProtKB. DR GO; GO:0005813; C:centrosome; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0030425; C:dendrite; ISS:ARUK-UCL. DR GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO. DR GO; GO:0005739; C:mitochondrion; IEA:GOC. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0098794; C:postsynapse; IEA:GOC. DR GO; GO:0098793; C:presynapse; IEA:GOC. DR GO; GO:1990909; C:Wnt signalosome; TAS:ParkinsonsUK-UCL. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0008013; F:beta-catenin binding; IPI:BHF-UCL. DR GO; GO:0034452; F:dynactin binding; IPI:ARUK-UCL. DR GO; GO:0016301; F:kinase activity; IDA:UniProtKB. DR GO; GO:0051059; F:NF-kappaB binding; IPI:UniProtKB. DR GO; GO:0002039; F:p53 binding; IDA:MGI. DR GO; GO:0002020; F:protease binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0034236; F:protein kinase A catalytic subunit binding; IPI:BHF-UCL. DR GO; GO:0004672; F:protein kinase activity; IMP:UniProtKB. DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB. DR GO; GO:0106310; F:protein serine kinase activity; IGI:ARUK-UCL. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:UniProtKB. DR GO; GO:0097110; F:scaffold protein binding; IPI:BHF-UCL. DR GO; GO:0048156; F:tau protein binding; NAS:ARUK-UCL. DR GO; GO:0050321; F:tau-protein kinase activity; IDA:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:BHF-UCL. DR GO; GO:0160213; P:beta-arrestin-dependent dopamine receptor signaling pathway; NAS:ParkinsonsUK-UCL. DR GO; GO:0060070; P:canonical Wnt signaling pathway; IDA:BHF-UCL. DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central. DR GO; GO:1904646; P:cellular response to amyloid-beta; ISS:ARUK-UCL. DR GO; GO:0036016; P:cellular response to interleukin-3; ISS:UniProtKB. DR GO; GO:0071300; P:cellular response to retinoic acid; IMP:ARUK-UCL. DR GO; GO:0007623; P:circadian rhythm; ISS:UniProtKB. DR GO; GO:0001837; P:epithelial to mesenchymal transition; IMP:UniProtKB. DR GO; GO:0006983; P:ER overload response; IDA:MGI. DR GO; GO:0030010; P:establishment of cell polarity; ISS:ARUK-UCL. DR GO; GO:0060079; P:excitatory postsynaptic potential; NAS:ParkinsonsUK-UCL. DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; ISS:ARUK-UCL. DR GO; GO:0097192; P:extrinsic apoptotic signaling pathway in absence of ligand; ISS:UniProtKB. DR GO; GO:0005977; P:glycogen metabolic process; IDA:BHF-UCL. DR GO; GO:0003170; P:heart valve development; ISS:BHF-UCL. DR GO; GO:0021766; P:hippocampus development; IMP:BHF-UCL. DR GO; GO:0008286; P:insulin receptor signaling pathway; IBA:GO_Central. DR GO; GO:0035556; P:intracellular signal transduction; IDA:MGI. DR GO; GO:0030011; P:maintenance of cell polarity; ISS:ARUK-UCL. DR GO; GO:0007005; P:mitochondrion organization; IMP:ParkinsonsUK-UCL. DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:MGI. DR GO; GO:0070885; P:negative regulation of calcineurin-NFAT signaling cascade; IMP:UniProtKB. DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IMP:ARUK-UCL. DR GO; GO:0030336; P:negative regulation of cell migration; IDA:UniProt. DR GO; GO:1904339; P:negative regulation of dopaminergic neuron differentiation; TAS:ParkinsonsUK-UCL. DR GO; GO:0010719; P:negative regulation of epithelial to mesenchymal transition; IDA:UniProtKB. DR GO; GO:1902042; P:negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; IMP:UniProtKB. DR GO; GO:0010629; P:negative regulation of gene expression; IMP:ARUK-UCL. DR GO; GO:2000466; P:negative regulation of glycogen (starch) synthase activity; TAS:UniProtKB. DR GO; GO:0045719; P:negative regulation of glycogen biosynthetic process; TAS:UniProtKB. DR GO; GO:2000740; P:negative regulation of mesenchymal stem cell differentiation; IMP:ARUK-UCL. DR GO; GO:0045668; P:negative regulation of osteoblast differentiation; IMP:ARUK-UCL. DR GO; GO:1900181; P:negative regulation of protein localization to nucleus; ISS:BHF-UCL. DR GO; GO:0031333; P:negative regulation of protein-containing complex assembly; IMP:BHF-UCL. DR GO; GO:0032007; P:negative regulation of TOR signaling; IBA:GO_Central. DR GO; GO:1903940; P:negative regulation of TORC2 signaling; IDA:UniProtKB. DR GO; GO:2000077; P:negative regulation of type B pancreatic cell development; TAS:UniProtKB. DR GO; GO:0031175; P:neuron projection development; IDA:UniProtKB. DR GO; GO:0106027; P:neuron projection organization; ISS:ARUK-UCL. DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:MGI. DR GO; GO:0010508; P:positive regulation of autophagy; ISS:UniProtKB. DR GO; GO:0045597; P:positive regulation of cell differentiation; IMP:ARUK-UCL. DR GO; GO:0001954; P:positive regulation of cell-matrix adhesion; IMP:BHF-UCL. DR GO; GO:0045724; P:positive regulation of cilium assembly; ISS:UniProtKB. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:ARUK-UCL. DR GO; GO:1901030; P:positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway; ISS:UniProtKB. DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IBA:GO_Central. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IDA:FlyBase. DR GO; GO:0032092; P:positive regulation of protein binding; ISS:UniProtKB. DR GO; GO:0045732; P:positive regulation of protein catabolic process; IC:BHF-UCL. DR GO; GO:0046827; P:positive regulation of protein export from nucleus; IDA:MGI. DR GO; GO:1904781; P:positive regulation of protein localization to centrosome; IMP:ARUK-UCL. DR GO; GO:1903566; P:positive regulation of protein localization to cilium; ISS:UniProtKB. DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IDA:UniProt. DR GO; GO:0031334; P:positive regulation of protein-containing complex assembly; IDA:BHF-UCL. DR GO; GO:0032481; P:positive regulation of type I interferon production; ISS:UniProtKB. DR GO; GO:0099171; P:presynaptic modulation of chemical synaptic transmission; IDA:SynGO. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; NAS:ComplexPortal. DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB. DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB. DR GO; GO:0030516; P:regulation of axon extension; ISS:ARUK-UCL. DR GO; GO:0050770; P:regulation of axonogenesis; ISS:ARUK-UCL. DR GO; GO:1900034; P:regulation of cellular response to heat; TAS:Reactome. DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB. DR GO; GO:0048814; P:regulation of dendrite morphogenesis; ISS:ARUK-UCL. DR GO; GO:1900271; P:regulation of long-term synaptic potentiation; ISS:UniProtKB. DR GO; GO:0150101; P:regulation of microtubule anchoring at centrosome; IMP:ARUK-UCL. DR GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; ISS:ARUK-UCL. DR GO; GO:0032886; P:regulation of microtubule-based process; IMP:UniProtKB. DR GO; GO:0010975; P:regulation of neuron projection development; IBA:GO_Central. DR GO; GO:0046825; P:regulation of protein export from nucleus; IDA:ComplexPortal. DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IDA:UniProt. DR GO; GO:0071109; P:superior temporal gyrus development; IMP:BHF-UCL. DR GO; GO:0019082; P:viral protein processing; TAS:Reactome. DR GO; GO:0016055; P:Wnt signaling pathway; IMP:BHF-UCL. DR CDD; cd14137; STKc_GSK3; 1. DR DisProt; DP00385; -. DR FunFam; 1.10.510.10:FF:000055; Glycogen synthase kinase-3 beta; 1. DR FunFam; 3.30.200.20:FF:000009; Glycogen synthase kinase-3 beta; 1. DR Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR IDEAL; IID00052; -. DR InterPro; IPR050591; GSK-3. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR InterPro; IPR039192; STKc_GSK3. DR PANTHER; PTHR24057; GLYCOGEN SYNTHASE KINASE-3 ALPHA; 1. DR PANTHER; PTHR24057:SF8; GLYCOGEN SYNTHASE KINASE-3 BETA; 1. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. PE 1: Evidence at protein level; KW 3D-structure; ADP-ribosylation; Alternative splicing; Alzheimer disease; KW ATP-binding; Biological rhythms; Carbohydrate metabolism; Cell membrane; KW Cytoplasm; Developmental protein; Diabetes mellitus; Differentiation; KW Glycogen metabolism; Kinase; Lipoprotein; Membrane; Neurogenesis; KW Nucleotide-binding; Nucleus; Palmitate; Phosphoprotein; KW Proteomics identification; Reference proteome; KW Serine/threonine-protein kinase; Signal transduction inhibitor; KW Transferase; Wnt signaling pathway. FT CHAIN 1..420 FT /note="Glycogen synthase kinase-3 beta" FT /id="PRO_0000085980" FT DOMAIN 56..340 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REGION 1..53 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 386..420 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1..22 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 386..401 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 409..420 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 181 FT /note="Proton acceptor" FT BINDING 62..70 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 85 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000305|PubMed:17050006" FT MOD_RES 9 FT /note="Phosphoserine; by PKB/AKT1, RPS6KA3, SGK3 and NME7" FT /evidence="ECO:0000269|PubMed:12054501, FT ECO:0000269|PubMed:16484495, ECO:0000269|PubMed:20937854, FT ECO:0000269|PubMed:24391509, ECO:0000269|PubMed:25169422, FT ECO:0000269|PubMed:34764205, ECO:0000269|PubMed:35606353, FT ECO:0000269|PubMed:8250835" FT MOD_RES 216 FT /note="Phosphotyrosine" FT /evidence="ECO:0000269|PubMed:12554650, FT ECO:0000269|PubMed:25169422" FT MOD_RES 389 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9WV60" FT MOD_RES 390 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 402 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18691976" FT LIPID 14 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:35606353" FT VAR_SEQ 303 FT /note="K -> KDSSGTGHFTSGVR (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_004790" FT MUTAGEN 9 FT /note="S->A: Loss of phosphorylation; abolished inhibition FT of activity, leading to constitutively active." FT /evidence="ECO:0000269|PubMed:17050006, FT ECO:0000269|PubMed:28992046, ECO:0000269|PubMed:7980435" FT MUTAGEN 14 FT /note="C->A: Significantly reduced palmitoylation." FT /evidence="ECO:0000269|PubMed:35606353" FT MUTAGEN 85..86 FT /note="KK->AA: Abolished serine/threonine-protein kinase FT activity." FT /evidence="ECO:0000269|PubMed:17050006" FT MUTAGEN 96 FT /note="R->A: Prevents the phosphorylation of phosphate- FT primed glycogen synthase." FT /evidence="ECO:0000269|PubMed:11430833" FT MUTAGEN 128 FT /note="L->A: Abolishes activity toward AXIN1." FT /evidence="ECO:0000269|PubMed:11430833" FT CONFLICT 28 FT /note="V -> G (in Ref. 4; AAD48517)" FT /evidence="ECO:0000305" FT CONFLICT 350 FT /note="L -> H (in Ref. 1; AAA66475)" FT /evidence="ECO:0000305" FT STRAND 10..12 FT /evidence="ECO:0007829|PDB:2JDO" FT STRAND 26..30 FT /evidence="ECO:0007829|PDB:1J1B" FT STRAND 32..34 FT /evidence="ECO:0007829|PDB:4NM5" FT STRAND 38..48 FT /evidence="ECO:0007829|PDB:1J1B" FT STRAND 52..64 FT /evidence="ECO:0007829|PDB:1J1B" FT STRAND 66..75 FT /evidence="ECO:0007829|PDB:1J1B" FT TURN 76..78 FT /evidence="ECO:0007829|PDB:1J1B" FT STRAND 81..88 FT /evidence="ECO:0007829|PDB:1J1B" FT STRAND 91..93 FT /evidence="ECO:0007829|PDB:1Q5K" FT HELIX 96..102 FT /evidence="ECO:0007829|PDB:1J1B" FT STRAND 112..120 FT /evidence="ECO:0007829|PDB:1J1B" FT TURN 121..124 FT /evidence="ECO:0007829|PDB:1J1B" FT STRAND 125..133 FT /evidence="ECO:0007829|PDB:1J1B" FT STRAND 136..138 FT /evidence="ECO:0007829|PDB:7SXJ" FT HELIX 139..148 FT /evidence="ECO:0007829|PDB:1J1B" FT HELIX 155..173 FT /evidence="ECO:0007829|PDB:1J1B" FT TURN 174..176 FT /evidence="ECO:0007829|PDB:1J1B" FT HELIX 184..186 FT /evidence="ECO:0007829|PDB:1J1B" FT STRAND 187..190 FT /evidence="ECO:0007829|PDB:1J1B" FT TURN 191..194 FT /evidence="ECO:0007829|PDB:1J1B" FT STRAND 195..198 FT /evidence="ECO:0007829|PDB:1J1B" FT HELIX 201..203 FT /evidence="ECO:0007829|PDB:7SXJ" FT STRAND 209..211 FT /evidence="ECO:0007829|PDB:6HK4" FT HELIX 220..222 FT /evidence="ECO:0007829|PDB:7SXJ" FT HELIX 225..228 FT /evidence="ECO:0007829|PDB:1J1B" FT HELIX 237..252 FT /evidence="ECO:0007829|PDB:1J1B" FT HELIX 262..273 FT /evidence="ECO:0007829|PDB:1J1B" FT HELIX 278..284 FT /evidence="ECO:0007829|PDB:1J1B" FT HELIX 286..288 FT /evidence="ECO:0007829|PDB:7B6F" FT STRAND 289..291 FT /evidence="ECO:0007829|PDB:4ACC" FT HELIX 301..304 FT /evidence="ECO:0007829|PDB:1J1B" FT HELIX 311..320 FT /evidence="ECO:0007829|PDB:1J1B" FT HELIX 325..327 FT /evidence="ECO:0007829|PDB:1J1B" FT HELIX 331..335 FT /evidence="ECO:0007829|PDB:1J1B" FT HELIX 338..344 FT /evidence="ECO:0007829|PDB:1J1B" FT STRAND 345..347 FT /evidence="ECO:0007829|PDB:1UV5" FT STRAND 353..355 FT /evidence="ECO:0007829|PDB:6HK4" FT HELIX 364..367 FT /evidence="ECO:0007829|PDB:1J1B" FT HELIX 371..373 FT /evidence="ECO:0007829|PDB:1J1B" FT HELIX 374..377 FT /evidence="ECO:0007829|PDB:1J1B" FT TURN 380..383 FT /evidence="ECO:0007829|PDB:1J1B" SQ SEQUENCE 420 AA; 46744 MW; 4ACC24D00CDBB9C3 CRC64; MSGRPRTTSF AESCKPVQQP SAFGSMKVSR DKDGSKVTTV VATPGQGPDR PQEVSYTDTK VIGNGSFGVV YQAKLCDSGE LVAIKKVLQD KRFKNRELQI MRKLDHCNIV RLRYFFYSSG EKKDEVYLNL VLDYVPETVY RVARHYSRAK QTLPVIYVKL YMYQLFRSLA YIHSFGICHR DIKPQNLLLD PDTAVLKLCD FGSAKQLVRG EPNVSYICSR YYRAPELIFG ATDYTSSIDV WSAGCVLAEL LLGQPIFPGD SGVDQLVEII KVLGTPTREQ IREMNPNYTE FKFPQIKAHP WTKVFRPRTP PEAIALCSRL LEYTPTARLT PLEACAHSFF DELRDPNVKL PNGRDTPALF NFTTQELSSN PPLATILIPP HARIQAAAST PTNATAASDA NTGDRGQTNN AASASASNST // ID KC1D_HUMAN Reviewed; 415 AA. AC P48730; A2I2P2; Q96KZ6; Q9BTN5; DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot. DT 27-JAN-2003, sequence version 2. DT 28-JAN-2026, entry version 234. DE RecName: Full=Casein kinase I isoform delta; DE Short=CKI-delta; DE Short=CKId; DE EC=2.7.11.1 {ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:17562708, ECO:0000269|PubMed:20041275, ECO:0000269|PubMed:20637175, ECO:0000269|PubMed:21422228, ECO:0000269|PubMed:23636092}; DE AltName: Full=Tau-protein kinase CSNK1D; DE EC=2.7.11.26 {ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:16618118, ECO:0000269|PubMed:17562708}; GN Name=CSNK1D; Synonyms=HCKID; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=8786104; DOI=10.1006/geno.1996.0091; RA Kusuda J., Hidari N., Hidari M., Hashimoto K.; RT "Sequence analysis of the cDNA for the human casein kinase I delta (CSNK1D) RT gene and its chromosomal localization."; RL Genomics 32:140-143(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY. RC TISSUE=Hematopoietic stem cell; RX PubMed=15070676; DOI=10.1182/blood-2003-08-2768; RA Okamura A., Iwata N., Nagata A., Tamekane A., Shimoyama M., Gomyo H., RA Yakushijin K., Urahama N., Hamaguchi M., Fukui C., Chihara K., Ito M., RA Matsui T.; RT "Involvement of casein kinase Iepsilon in cytokine-induced granulocytic RT differentiation."; RL Blood 103:2997-3004(2004). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NHLBI resequencing and genotyping service (RS&G); RL Submitted (SEP-2006) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Placenta; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Placenta, and Spleen; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP ACTIVITY REGULATION, AND AUTOPHOSPHORYLATION. RX PubMed=9632646; DOI=10.1074/jbc.273.26.15980; RA Rivers A., Gietzen K.F., Vielhaber E., Virshup D.M.; RT "Regulation of casein kinase I epsilon and casein kinase I delta by an in RT vivo futile phosphorylation cycle."; RL J. Biol. Chem. 273:15980-15984(1998). RN [7] RP FUNCTION AS TP53 KINASE, AND CATALYTIC ACTIVITY. RX PubMed=10606744; DOI=10.1016/s0014-5793(99)01647-6; RA Dumaz N., Milne D.M., Meek D.W.; RT "Protein kinase CK1 is a p53-threonine 18 kinase which requires prior RT phosphorylation of serine 15."; RL FEBS Lett. 463:312-316(1999). RN [8] RP INTERACTION WITH TUBULINS, AND SUBCELLULAR LOCATION. RX PubMed=10826492; DOI=10.1078/s0171-9335(04)70027-8; RA Behrend L., Stoeter M., Kurth M., Rutter G., Heukeshoven J., Deppert W., RA Knippschild U.; RT "Interaction of casein kinase 1 delta (CK1delta) with post-Golgi RT structures, microtubules and the spindle apparatus."; RL Eur. J. Cell Biol. 79:240-251(2000). RN [9] RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-38 AND THR-176. RX PubMed=11161704; DOI=10.1006/excr.2000.5100; RA Milne D.M., Looby P., Meek D.W.; RT "Catalytic activity of protein kinase CK1 delta (casein kinase 1delta) is RT essential for its normal subcellular localization."; RL Exp. Cell Res. 263:43-54(2001). RN [10] RP INTERACTION WITH PER1 AND PER2. RX PubMed=11165242; DOI=10.1016/s0014-5793(00)02434-0; RA Camacho F., Cilio M., Guo Y., Virshup D.M., Patel K., Khorkova O., RA Styren S., Morse B., Yao Z., Keesler G.A.; RT "Human casein kinase Idelta phosphorylation of human circadian clock RT proteins period 1 and 2."; RL FEBS Lett. 489:159-165(2001). RN [11] RP FUNCTION AS CONNEXIN-43/GJA1 KINASE, INTERACTION WITH CONNEXIN-43/GJA1, AND RP CATALYTIC ACTIVITY. RX PubMed=12270943; DOI=10.1074/jbc.m209427200; RA Cooper C.D., Lampe P.D.; RT "Casein kinase 1 regulates connexin-43 gap junction assembly."; RL J. Biol. Chem. 277:44962-44968(2002). RN [12] RP INTERACTION WITH AKAP9/AKAP450, AND SUBCELLULAR LOCATION. RX PubMed=12270714; DOI=10.1016/s0022-2836(02)00857-4; RA Sillibourne J.E., Milne D.M., Takahashi M., Ono Y., Meek D.W.; RT "Centrosomal anchoring of the protein kinase CK1delta mediated by RT attachment to the large, coiled-coil scaffolding protein CG-NAP/AKAP450."; RL J. Mol. Biol. 322:785-797(2002). RN [13] RP IDENTIFICATION BY MASS SPECTROMETRY, AND SUBCELLULAR LOCATION [LARGE SCALE RP ANALYSIS]. RC TISSUE=Lymphoblast; RX PubMed=14654843; DOI=10.1038/nature02166; RA Andersen J.S., Wilkinson C.J., Mayor T., Mortensen P., Nigg E.A., Mann M.; RT "Proteomic characterization of the human centrosome by protein correlation RT profiling."; RL Nature 426:570-574(2003). RN [14] RP FUNCTION AS MAPT/TAU KINASE, ACTIVITY REGULATION, INTERACTION WITH RP MAPT/TAU, AND CATALYTIC ACTIVITY. RX PubMed=14761950; DOI=10.1074/jbc.m314116200; RA Li G., Yin H., Kuret J.; RT "Casein kinase 1 delta phosphorylates tau and disrupts its binding to RT microtubules."; RL J. Biol. Chem. 279:15938-15945(2004). RN [15] RP FUNCTION IN MITOTIC SPINDLE FORMATION, SUBCELLULAR LOCATION, TISSUE RP SPECIFICITY, DEVELOPMENTAL STAGE, AND ACTIVITY REGULATION. RX PubMed=16027726; DOI=10.1038/sj.onc.1208941; RA Stoeter M., Bamberger A.-M., Aslan B., Kurth M., Speidel D., Loening T., RA Frank H.-G., Kaufmann P., Loehler J., Henne-Bruns D., Deppert W., RA Knippschild U.; RT "Inhibition of casein kinase I delta alters mitotic spindle formation and RT induces apoptosis in trophoblast cells."; RL Oncogene 24:7964-7975(2005). RN [16] RP CATALYTIC ACTIVITY, AND INTERACTION WITH DBNDD2. RX PubMed=16618118; DOI=10.1021/bi052354e; RA Yin H., Laguna K.A., Li G., Kuret J.; RT "Dysbindin structural homologue CK1BP is an isoform-selective binding RT partner of human casein kinase-1."; RL Biochemistry 45:5297-5308(2006). RN [17] RP FUNCTION AS PKD2 KINASE, AND CATALYTIC ACTIVITY. RX PubMed=17962809; DOI=10.1038/sj.emboj.7601891; RA von Blume J., Knippschild U., Dequiedt F., Giamas G., Beck A., Auer A., RA Van Lint J., Adler G., Seufferlein T.; RT "Phosphorylation at Ser244 by CK1 determines nuclear localization and RT substrate targeting of PKD2."; RL EMBO J. 26:4619-4633(2007). RN [18] RP FUNCTION AS MAPT/TAU KINASE, AND CATALYTIC ACTIVITY. RX PubMed=17562708; DOI=10.1074/jbc.m703269200; RA Hanger D.P., Byers H.L., Wray S., Leung K.-Y., Saxton M.J., Seereeram A., RA Reynolds C.H., Ward M.A., Anderton B.H.; RT "Novel phosphorylation sites in tau from Alzheimer brain support a role for RT casein kinase 1 in disease pathogenesis."; RL J. Biol. Chem. 282:23645-23654(2007). RN [19] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18220336; DOI=10.1021/pr0705441; RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III; RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient RT phosphoproteomic analysis."; RL J. Proteome Res. 7:1346-1351(2008). RN [20] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [21] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-331 AND SER-384, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [22] RP ACTIVITY REGULATION, AND CATALYTIC ACTIVITY. RX PubMed=19591487; DOI=10.1021/jm9005127; RA Peifer C., Abadleh M., Bischof J., Hauser D., Schattel V., Hirner H., RA Knippschild U., Laufer S.; RT "3,4-Diaryl-isoxazoles and -imidazoles as potent dual inhibitors of RT p38alpha mitogen activated protein kinase and casein kinase 1delta."; RL J. Med. Chem. 52:7618-7630(2009). RN [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-411, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [24] RP FUNCTION AS TOP2A KINASE, ACTIVITY REGULATION, AND CATALYTIC ACTIVITY. RX PubMed=19043076; DOI=10.1093/nar/gkn934; RA Grozav A.G., Chikamori K., Kozuki T., Grabowski D.R., Bukowski R.M., RA Willard B., Kinter M., Andersen A.H., Ganapathi R., Ganapathi M.K.; RT "Casein kinase I delta/epsilon phosphorylates topoisomerase IIalpha at RT serine-1106 and modulates DNA cleavage activity."; RL Nucleic Acids Res. 37:382-392(2009). RN [25] RP RETRACTED PAPER. RX PubMed=19339517; DOI=10.1093/nar/gkp136; RA Giamas G., Castellano L., Feng Q., Knippschild U., Jacob J., Thomas R.S., RA Coombes R.C., Smith C.L., Jiao L.R., Stebbing J.; RT "CK1delta modulates the transcriptional activity of ERalpha via AIB1 in an RT estrogen-dependent manner and regulates ERalpha-AIB1 interactions."; RL Nucleic Acids Res. 37:3110-3123(2009). RN [26] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-383, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [27] RP FUNCTION AS DCK KINASE, AND CATALYTIC ACTIVITY. RX PubMed=20637175; DOI=10.1016/j.abb.2010.07.009; RA Smal C., Vertommen D., Amsailale R., Arts A., Degand H., Morsomme P., RA Rider M.H., Neste E.V., Bontemps F.; RT "Casein kinase 1delta activates human recombinant deoxycytidine kinase by RT Ser-74 phosphorylation, but is not involved in the in vivo regulation of RT its activity."; RL Arch. Biochem. Biophys. 502:44-52(2010). RN [28] RP FUNCTION AS P53/TP53 KINASE, GENE FAMILY, AND CATALYTIC ACTIVITY. RX PubMed=20041275; DOI=10.1007/s00018-009-0236-7; RA Venerando A., Marin O., Cozza G., Bustos V.H., Sarno S., Pinna L.A.; RT "Isoform specific phosphorylation of p53 by protein kinase CK1."; RL Cell. Mol. Life Sci. 67:1105-1118(2010). RN [29] RP FUNCTION AS YAP1 KINASE, AND CATALYTIC ACTIVITY. RX PubMed=20048001; DOI=10.1101/gad.1843810; RA Zhao B., Li L., Tumaneng K., Wang C.-Y., Guan K.-L.; RT "A coordinated phosphorylation by Lats and CK1 regulates YAP stability RT through SCF(beta-TRCP)."; RL Genes Dev. 24:72-85(2010). RN [30] RP FUNCTION AS HIF1A KINASE, AND CATALYTIC ACTIVITY. RX PubMed=20699359; DOI=10.1242/jcs.068122; RA Kalousi A., Mylonis I., Politou A.S., Chachami G., Paraskeva E., Simos G.; RT "Casein kinase 1 regulates human hypoxia-inducible factor HIF-1."; RL J. Cell Sci. 123:2976-2986(2010). RN [31] RP FUNCTION IN CIRCADIAN RHYTHMS, AND ACTIVITY REGULATION. RX PubMed=20696890; DOI=10.1073/pnas.1005101107; RA Meng Q.-J., Maywood E.S., Bechtold D.A., Lu W.-Q., Li J., Gibbs J.E., RA Dupre S.M., Chesham J.E., Rajamohan F., Knafels J., Sneed B., RA Zawadzke L.E., Ohren J.F., Walton K.M., Wager T.T., Hastings M.H., RA Loudon A.S.I.; RT "Entrainment of disrupted circadian behavior through inhibition of casein RT kinase 1 (CK1) enzymes."; RL Proc. Natl. Acad. Sci. U.S.A. 107:15240-15245(2010). RN [32] RP FUNCTION IN CIRCADIAN RHYTHMS, AND ACTIVITY REGULATION. RX PubMed=20407760; DOI=10.1007/s00213-010-1860-5; RA Sprouse J., Reynolds L., Kleiman R., Tate B., Swanson T.A., Pickard G.E.; RT "Chronic treatment with a selective inhibitor of casein kinase I RT delta/epsilon yields cumulative phase delays in circadian rhythms."; RL Psychopharmacology 210:569-576(2010). RN [33] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [34] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [35] RP FUNCTION AS EIF6 KINASE, ACTIVITY REGULATION, AND CATALYTIC ACTIVITY. RX PubMed=21084295; DOI=10.1074/jbc.m110.188565; RA Biswas A., Mukherjee S., Das S., Shields D., Chow C.W., Maitra U.; RT "Opposing action of casein kinase 1 and calcineurin in nucleo-cytoplasmic RT shuttling of mammalian translation initiation factor eIF6."; RL J. Biol. Chem. 286:3129-3138(2011). RN [36] RP FUNCTION AS DVL2 AND DVL3 KINASE, ACTIVITY REGULATION, SUBCELLULAR RP LOCATION, AND CATALYTIC ACTIVITY. RX PubMed=21422228; DOI=10.1083/jcb.201011111; RA Greer Y.E., Rubin J.S.; RT "Casein kinase 1 delta functions at the centrosome to mediate Wnt-3a- RT dependent neurite outgrowth."; RL J. Cell Biol. 192:993-1004(2011). RN [37] RP ACTIVITY REGULATION, AND AUTOPHOSPHORYLATION. RX PubMed=21258417; DOI=10.1038/onc.2010.627; RA Cheong J.K., Nguyen T.H., Wang H., Tan P., Voorhoeve P.M., Lee S.H., RA Virshup D.M.; RT "IC261 induces cell cycle arrest and apoptosis of human cancer cells via RT CK1delta/epsilon and Wnt/beta-catenin independent inhibition of mitotic RT spindle formation."; RL Oncogene 30:2558-2569(2011). RN [38] RP REVIEW ON CIRCADIAN RHYTHMS, AND GENE FAMILY. RX PubMed=21145983; DOI=10.1016/j.biocel.2010.12.004; RA Cheong J.K., Virshup D.M.; RT "Casein kinase 1: Complexity in the family."; RL Int. J. Biochem. Cell Biol. 43:465-469(2011). RN [39] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-328; SER-331; SER-382; RP SER-384 AND SER-407, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [40] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [41] RP INTERACTION WITH DDX3X. RX PubMed=29222110; DOI=10.1242/jcs.207316; RA Dolde C., Bischof J., Grueter S., Montada A., Halekotte J., Peifer C., RA Kalbacher H., Baumann U., Knippschild U., Suter B.; RT "A CK1 FRET biosensor reveals that DDX3X is an essential activator of RT CK1epsilon."; RL J. Cell Sci. 131:0-0(2018). RN [42] RP INTERACTION WITH FAM83A; FAM83B; FAM83E AND FAM83H. RX PubMed=29789297; DOI=10.1126/scisignal.aao2341; RA Fulcher L.J., Bozatzi P., Tachie-Menson T., Wu K.Z.L., Cummins T.D., RA Bufton J.C., Pinkas D.M., Dunbar K., Shrestha S., Wood N.T., Weidlich S., RA Macartney T.J., Varghese J., Gourlay R., Campbell D.G., Dingwell K.S., RA Smith J.C., Bullock A.N., Sapkota G.P.; RT "The DUF1669 domain of FAM83 family proteins anchor casein kinase 1 RT isoforms."; RL Sci. Signal. 11:0-0(2018). RN [43] RP RETRACTION NOTICE OF PUBMED:19339517. RX PubMed=34718754; DOI=10.1093/nar/gkab845; RA Giamas G., Castellano L., Feng Q., Knippschild U., Jacob J., Thomas R.S., RA Coombes R.C., Smith C.L., Jiao L.R., Stebbing J.; RT "Retraction of 'CK1delta modulates the transcriptional activity of ERalpha RT via AIB1 in an estrogen-dependent manner and regulates ERalpha-AIB1 RT interactions'."; RL Nucleic Acids Res. 49:12006-12006(2021). RN [44] RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS). RX PubMed=9761932; DOI=10.1107/s0907444997011724; RA Longenecker K.L., Roach P.J., Hurley T.D.; RT "Crystallographic studies of casein kinase I delta toward a structural RT understanding of auto-inhibition."; RL Acta Crystallogr. D 54:473-475(1998). RN [45] RP X-RAY CRYSTALLOGRAPHY (1.94 ANGSTROMS) OF 1-294 IN COMPLEX WITH INHIBITOR, RP AND SUBUNIT. RX PubMed=22168824; DOI=10.1021/jm201387s; RA Long A., Zhao H., Huang X.; RT "Structural basis for the interaction between casein kinase 1 delta and a RT potent and selective inhibitor."; RL J. Med. Chem. 55:956-960(2012). RN [46] RP X-RAY CRYSTALLOGRAPHY (2.07 ANGSTROMS) OF 1-294 IN COMPLEX WITH INHIBITOR, RP AND SUBUNIT. RX PubMed=23106386; DOI=10.1021/jm301336n; RA Long A.M., Zhao H., Huang X.; RT "Structural basis for the potent and selective inhibition of casein kinase RT 1 epsilon."; RL J. Med. Chem. 55:10307-10311(2012). RN [47] RP VARIANT FASPS2 ALA-44. RX PubMed=15800623; DOI=10.1038/nature03453; RA Xu Y., Padiath Q.S., Shapiro R.E., Jones C.R., Wu S.C., Saigoh N., RA Saigoh K., Ptacek L.J., Fu Y.H.; RT "Functional consequences of a CKIdelta mutation causing familial advanced RT sleep phase syndrome."; RL Nature 434:640-644(2005). RN [48] RP VARIANT [LARGE SCALE ANALYSIS] CYS-97. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). RN [49] RP VARIANTS [LARGE SCALE ANALYSIS] CYS-97 AND ALA-401. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [50] RP VARIANTS FASPS2 ALA-44 AND ARG-46, CHARACTERIZATION OF VARIANTS FASPS2 RP ALA-44 AND ARG-46, FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL RP PROPERTIES. RX PubMed=23636092; DOI=10.1126/scitranslmed.3005784; RA Brennan K.C., Bates E.A., Shapiro R.E., Zyuzin J., Hallows W.C., Huang Y., RA Lee H.Y., Jones C.R., Fu Y.H., Charles A.C., Ptacek L.J.; RT "Casein kinase idelta mutations in familial migraine and advanced phase."; RL Sci. Transl. Med. 5:183ra56-183ra56(2013). CC -!- FUNCTION: Essential serine/threonine-protein kinase that regulates CC diverse cellular growth and survival processes including Wnt signaling, CC DNA repair and circadian rhythms. It can phosphorylate a large number CC of proteins. Casein kinases are operationally defined by their CC preferential utilization of acidic proteins such as caseins as CC substrates. Phosphorylates connexin-43/GJA1, MAP1A, SNAPIN, MAPT/TAU, CC TOP2A, DCK, HIF1A, EIF6, p53/TP53, DVL2, DVL3, ESR1, AIB1/NCOA3, DNMT1, CC PKD2, YAP1, PER1 and PER2. Central component of the circadian clock. In CC balance with PP1, determines the circadian period length through the CC regulation of the speed and rhythmicity of PER1 and PER2 CC phosphorylation. Controls PER1 and PER2 nuclear transport and CC degradation. YAP1 phosphorylation promotes its SCF(beta-TRCP) E3 CC ubiquitin ligase-mediated ubiquitination and subsequent degradation. CC DNMT1 phosphorylation reduces its DNA-binding activity. Phosphorylation CC of ESR1 and AIB1/NCOA3 stimulates their activity and coactivation. CC Phosphorylation of DVL2 and DVL3 regulates WNT3A signaling pathway that CC controls neurite outgrowth. Phosphorylates NEDD9/HEF1 (By similarity). CC EIF6 phosphorylation promotes its nuclear export. Triggers down- CC regulation of dopamine receptors in the forebrain. Activates DCK in CC vitro by phosphorylation. TOP2A phosphorylation favors DNA cleavable CC complex formation. May regulate the formation of the mitotic spindle CC apparatus in extravillous trophoblast. Modulates connexin-43/GJA1 gap CC junction assembly by phosphorylation. Probably involved in lymphocyte CC physiology. Regulates fast synaptic transmission mediated by glutamate. CC {ECO:0000250|UniProtKB:Q9DC28, ECO:0000269|PubMed:10606744, CC ECO:0000269|PubMed:12270943, ECO:0000269|PubMed:14761950, CC ECO:0000269|PubMed:16027726, ECO:0000269|PubMed:17562708, CC ECO:0000269|PubMed:17962809, ECO:0000269|PubMed:19043076, CC ECO:0000269|PubMed:20041275, ECO:0000269|PubMed:20048001, CC ECO:0000269|PubMed:20407760, ECO:0000269|PubMed:20637175, CC ECO:0000269|PubMed:20696890, ECO:0000269|PubMed:20699359, CC ECO:0000269|PubMed:21084295, ECO:0000269|PubMed:21422228, CC ECO:0000269|PubMed:23636092}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + CC H(+); Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:12270943, ECO:0000269|PubMed:14761950, CC ECO:0000269|PubMed:16618118, ECO:0000269|PubMed:17562708, CC ECO:0000269|PubMed:17962809, ECO:0000269|PubMed:19043076, CC ECO:0000269|PubMed:19591487, ECO:0000269|PubMed:20041275, CC ECO:0000269|PubMed:20048001, ECO:0000269|PubMed:20637175, CC ECO:0000269|PubMed:20699359, ECO:0000269|PubMed:21084295, CC ECO:0000269|PubMed:21422228, ECO:0000269|PubMed:23636092}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17990; CC Evidence={ECO:0000305|PubMed:20637175}; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + CC ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA- CC COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:10606744, ECO:0000269|PubMed:14761950, CC ECO:0000269|PubMed:17562708, ECO:0000269|PubMed:19591487, CC ECO:0000269|PubMed:20041275, ECO:0000269|PubMed:20637175, CC ECO:0000269|PubMed:21422228, ECO:0000269|PubMed:23636092}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46609; CC Evidence={ECO:0000305|PubMed:20637175}; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein] CC + ADP + H(+); Xref=Rhea:RHEA:12801, Rhea:RHEA-COMP:13701, Rhea:RHEA- CC COMP:13702, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.26; CC Evidence={ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:16618118, CC ECO:0000269|PubMed:17562708}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12802; CC Evidence={ECO:0000305|PubMed:14761950}; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-threonyl-[tau protein] + ATP = O-phospho-L-threonyl-[tau CC protein] + ADP + H(+); Xref=Rhea:RHEA:53904, Rhea:RHEA-COMP:13703, CC Rhea:RHEA-COMP:13704, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; CC EC=2.7.11.26; Evidence={ECO:0000269|PubMed:14761950, CC ECO:0000269|PubMed:16618118, ECO:0000269|PubMed:17562708}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53905; CC Evidence={ECO:0000305|PubMed:14761950}; CC -!- ACTIVITY REGULATION: Exhibits substrate-dependent heparin activation. CC Drug-mediated inhibition leads to a delay of the oscillations with the CC magnitude of this effect dependent upon the timing of drug CC administration. Inhibited by phosphorylation. Repressed by 3-[(2,4,6- CC trimethoxyphenyl)methylidenyl]-indolin-2-one (IC261), N-(2-aminoethyl)- CC 5-chloroisoquinoline-8-sulfonamide (CKI-7), 4-[4-(2,3-dihydro- CC benzo[1,4]dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide CC (D4476), 3,4-diaryl-isoxazoles and -imidazoles, and 4-(3-cyclohexyl-5- CC (4-fluoro-phenyl)-3H-imidazol-4-yl) pyrimidin-2-ylamine (PF670462, CC PF670). {ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:16027726, CC ECO:0000269|PubMed:19043076, ECO:0000269|PubMed:19591487, CC ECO:0000269|PubMed:20407760, ECO:0000269|PubMed:20696890, CC ECO:0000269|PubMed:21084295, ECO:0000269|PubMed:21258417, CC ECO:0000269|PubMed:21422228, ECO:0000269|PubMed:9632646}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=36.5 uM for alpha-casein {ECO:0000269|PubMed:23636092}; CC KM=635.8 uM for PER2 peptide {ECO:0000269|PubMed:23636092}; CC KM=180.6 uM for ATP {ECO:0000269|PubMed:23636092}; CC Note=Maximal velocity nearly identical for the reactions with alpha- CC casein and PER2 peptide.; CC -!- SUBUNIT: Monomer (PubMed:22168824, PubMed:23106386). Component of the CC circadian core oscillator, which includes the CRY proteins, CLOCK, or CC NPAS2, ARTNL/BMAL1 or ARTNL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS and CC the PER proteins (By similarity). Interacts with DNMT1 and MAP1A (By CC similarity). Interacts directly with PER1 and PER2 which may lead to CC their degradation (PubMed:11165242). Interacts with MAPT/TAU CC (PubMed:14761950). Interacts with SNAPIN (By similarity). Interacts CC with DBNDD2 (PubMed:16618118). Interacts with AKAP9/AKAP450; this CC interaction promotes centrosomal subcellular location CC (PubMed:12270714). Binds to tubulins in mitotic cells upon DNA damage CC (PubMed:10826492). Interacts with GJA1 (PubMed:12270943). Interacts CC with DDX3X; this interaction enhances CSNK1D kinase activity in vitro, CC but it is unclear whether this interaction is physiologically relevant CC (PubMed:29222110). Interacts with FAM83A, FAM83B, FAM83E and FAM83H CC (via DUF1669) (PubMed:29789297). {ECO:0000250|UniProtKB:Q06486, CC ECO:0000250|UniProtKB:Q9DC28, ECO:0000269|PubMed:10826492, CC ECO:0000269|PubMed:11165242, ECO:0000269|PubMed:12270714, CC ECO:0000269|PubMed:12270943, ECO:0000269|PubMed:14761950, CC ECO:0000269|PubMed:16618118, ECO:0000269|PubMed:22168824, CC ECO:0000269|PubMed:23106386, ECO:0000269|PubMed:29222110, CC ECO:0000269|PubMed:29789297}. CC -!- INTERACTION: CC P48730; P05067: APP; NbExp=3; IntAct=EBI-751621, EBI-77613; CC P48730; Q49A88-3: CCDC14; NbExp=3; IntAct=EBI-751621, EBI-12105646; CC P48730; Q6PGQ1: DRICH1; NbExp=3; IntAct=EBI-751621, EBI-10253641; CC P48730; Q92997: DVL3; NbExp=4; IntAct=EBI-751621, EBI-739789; CC P48730; O60447: EVI5; NbExp=3; IntAct=EBI-751621, EBI-852291; CC P48730; Q14C86: GAPVD1; NbExp=5; IntAct=EBI-751621, EBI-1049788; CC P48730; Q9H2S9: IKZF4; NbExp=3; IntAct=EBI-751621, EBI-1640423; CC P48730; Q96LR2: LURAP1; NbExp=4; IntAct=EBI-751621, EBI-741355; CC P48730; Q9BRK4: LZTS2; NbExp=3; IntAct=EBI-751621, EBI-741037; CC P48730; P23508: MCC; NbExp=6; IntAct=EBI-751621, EBI-307531; CC P48730; Q00987: MDM2; NbExp=6; IntAct=EBI-751621, EBI-389668; CC P48730; Q9P286: PAK5; NbExp=3; IntAct=EBI-751621, EBI-741896; CC P48730; O15055: PER2; NbExp=7; IntAct=EBI-751621, EBI-1054296; CC P48730; O75382: TRIM3; NbExp=3; IntAct=EBI-751621, EBI-2129889; CC P48730; Q9C026: TRIM9; NbExp=3; IntAct=EBI-751621, EBI-720828; CC P48730; P62258: YWHAE; NbExp=2; IntAct=EBI-751621, EBI-356498; CC P48730; Q96BR9: ZBTB8A; NbExp=3; IntAct=EBI-751621, EBI-742740; CC P48730; Q5T7W0: ZNF618; NbExp=4; IntAct=EBI-751621, EBI-6255994; CC P48730; Q60838: Dvl2; Xeno; NbExp=2; IntAct=EBI-751621, EBI-641940; CC P48730-2; P05067: APP; NbExp=3; IntAct=EBI-9087876, EBI-77613; CC P48730-2; Q92624: APPBP2; NbExp=3; IntAct=EBI-9087876, EBI-743771; CC P48730-2; Q96GW7: BCAN; NbExp=3; IntAct=EBI-9087876, EBI-2690445; CC P48730-2; Q8IU99: CALHM1; NbExp=3; IntAct=EBI-9087876, EBI-1790341; CC P48730-2; Q03135: CAV1; NbExp=3; IntAct=EBI-9087876, EBI-603614; CC P48730-2; P45973: CBX5; NbExp=3; IntAct=EBI-9087876, EBI-78219; CC P48730-2; P06850: CRH; NbExp=3; IntAct=EBI-9087876, EBI-3870390; CC P48730-2; Q01658: DR1; NbExp=3; IntAct=EBI-9087876, EBI-750300; CC P48730-2; Q9BS26: ERP44; NbExp=3; IntAct=EBI-9087876, EBI-541644; CC P48730-2; P35637: FUS; NbExp=3; IntAct=EBI-9087876, EBI-400434; CC P48730-2; P17302: GJA1; NbExp=3; IntAct=EBI-9087876, EBI-1103439; CC P48730-2; Q9H8Y8: GORASP2; NbExp=3; IntAct=EBI-9087876, EBI-739467; CC P48730-2; P25098: GRK2; NbExp=3; IntAct=EBI-9087876, EBI-3904795; CC P48730-2; Q00403: GTF2B; NbExp=3; IntAct=EBI-9087876, EBI-389564; CC P48730-2; Q9Y5Q9: GTF3C3; NbExp=3; IntAct=EBI-9087876, EBI-1054873; CC P48730-2; P42858: HTT; NbExp=15; IntAct=EBI-9087876, EBI-466029; CC P48730-2; Q14114-3: LRP8; NbExp=3; IntAct=EBI-9087876, EBI-25832196; CC P48730-2; Q5S007: LRRK2; NbExp=3; IntAct=EBI-9087876, EBI-5323863; CC P48730-2; Q16539: MAPK14; NbExp=3; IntAct=EBI-9087876, EBI-73946; CC P48730-2; Q96L34: MARK4; NbExp=3; IntAct=EBI-9087876, EBI-302319; CC P48730-2; P35240-4: NF2; NbExp=3; IntAct=EBI-9087876, EBI-1014514; CC P48730-2; Q6ZW49: PAXIP1; NbExp=3; IntAct=EBI-9087876, EBI-743225; CC P48730-2; O14494: PLPP1; NbExp=3; IntAct=EBI-9087876, EBI-2865290; CC P48730-2; A0A6Q8PF08: PMP22; NbExp=3; IntAct=EBI-9087876, EBI-50433196; CC P48730-2; P17612: PRKACA; NbExp=3; IntAct=EBI-9087876, EBI-476586; CC P48730-2; P07602: PSAP; NbExp=3; IntAct=EBI-9087876, EBI-716699; CC P48730-2; P54725: RAD23A; NbExp=3; IntAct=EBI-9087876, EBI-746453; CC P48730-2; P04271: S100B; NbExp=3; IntAct=EBI-9087876, EBI-458391; CC P48730-2; Q8WTV0: SCARB1; NbExp=3; IntAct=EBI-9087876, EBI-78657; CC P48730-2; P50454: SERPINH1; NbExp=3; IntAct=EBI-9087876, EBI-350723; CC P48730-2; Q8IUQ4-2: SIAH1; NbExp=3; IntAct=EBI-9087876, EBI-11522811; CC P48730-2; P84022: SMAD3; NbExp=3; IntAct=EBI-9087876, EBI-347161; CC P48730-2; P37840: SNCA; NbExp=3; IntAct=EBI-9087876, EBI-985879; CC P48730-2; P00441: SOD1; NbExp=3; IntAct=EBI-9087876, EBI-990792; CC P48730-2; Q6NUL7: SPTLC1; NbExp=3; IntAct=EBI-9087876, EBI-25912847; CC P48730-2; Q13148: TARDBP; NbExp=6; IntAct=EBI-9087876, EBI-372899; CC P48730-2; P37173: TGFBR2; NbExp=3; IntAct=EBI-9087876, EBI-296151; CC P48730-2; Q9NRS4: TMPRSS4; NbExp=3; IntAct=EBI-9087876, EBI-10313040; CC P48730-2; Q9BVJ6: UTP14A; NbExp=3; IntAct=EBI-9087876, EBI-473284; CC P48730-2; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-9087876, EBI-11141397; CC P48730-2; Q8IUH5: ZDHHC17; NbExp=3; IntAct=EBI-9087876, EBI-524753; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Cytoplasm, cytoskeleton, CC microtubule organizing center, centrosome CC {ECO:0000269|PubMed:14654843}. Cytoplasm, perinuclear region. Cell CC membrane. Cytoplasm, cytoskeleton, spindle. Golgi apparatus. CC Note=Localized at mitotic spindle microtubules, and at the centrosomes CC and interphase in interphase cells. Recruited to the spindle apparatus CC and the centrosomes in response to DNA-damage. Correct subcellular CC localization requires kinase activity. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P48730-1; Sequence=Displayed; CC Name=2; CC IsoId=P48730-2; Sequence=VSP_010253; CC -!- TISSUE SPECIFICITY: Expressed in all tissues examined, including brain, CC heart, lung, liver, pancreas, kidney, placenta and skeletal muscle. CC However, kinase activity is not uniform, with highest kinase activity CC in splenocytes. In blood, highly expressed in hemopoietic cells and CC mature granulocytes. Also found in monocytes and lymphocytes. CC {ECO:0000269|PubMed:15070676, ECO:0000269|PubMed:16027726}. CC -!- DEVELOPMENTAL STAGE: Highly present in extravillous trophoblast cells, CC which are present at the placenta implantation site and invade the CC decidua and decidual vessels. {ECO:0000269|PubMed:16027726}. CC -!- PTM: Autophosphorylated on serine and threonine residues; this CC autophosphorylation represses activity. Reactivated by phosphatase- CC mediated dephosphorylation. May be dephosphorylated by PP1. CC -!- DISEASE: Advanced sleep phase syndrome, familial, 2 (FASPS2) CC [MIM:615224]: An autosomal dominant disorder characterized by very CC early sleep onset and offset. Individuals are 'morning larks' with a 4 CC hours advance of the sleep, temperature and melatonin rhythms. CC {ECO:0000269|PubMed:15800623, ECO:0000269|PubMed:23636092}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- MISCELLANEOUS: May be involved in Alzheimer disease by phosphorylating CC MAPT/TAU. {ECO:0000305|PubMed:17562708}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CK1 Ser/Thr CC protein kinase family. Casein kinase I subfamily. {ECO:0000305}. CC -!- CAUTION: Was shown to phosphorylate and activate DCK in vitro but CC probably not in vivo. {ECO:0000305|PubMed:20637175}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U29171; AAC50807.1; -; mRNA. DR EMBL; U31285; AAC50808.1; -; mRNA. DR EMBL; AB091044; BAC10903.1; -; mRNA. DR EMBL; AK291758; BAF84447.1; -; mRNA. DR EMBL; EF015900; ABM64211.1; -; Genomic_DNA. DR EMBL; BC003558; AAH03558.1; -; mRNA. DR EMBL; BC015775; AAH15775.1; -; mRNA. DR CCDS; CCDS11805.1; -. [P48730-1] DR CCDS; CCDS11806.1; -. [P48730-2] DR PIR; G01876; G01876. DR RefSeq; NP_001884.2; NM_001893.4. [P48730-1] DR RefSeq; NP_620693.1; NM_139062.4. [P48730-2] DR PDB; 3UYS; X-ray; 2.30 A; A/B/C/D=1-294. DR PDB; 3UYT; X-ray; 2.00 A; A/B/C/D=1-294. DR PDB; 3UZP; X-ray; 1.94 A; A/B=1-294. DR PDB; 4HGT; X-ray; 1.80 A; A/B=1-294. DR PDB; 4HNF; X-ray; 2.07 A; A/B=1-294. DR PDB; 4KB8; X-ray; 1.95 A; A/B/C/D=3-317. DR PDB; 4KBA; X-ray; 1.98 A; A/B/C/D=3-317. DR PDB; 4KBC; X-ray; 1.98 A; A/B=1-317. DR PDB; 4KBK; X-ray; 2.10 A; A/B/C/D=3-317. DR PDB; 4TN6; X-ray; 2.41 A; A/B=1-301. DR PDB; 4TW9; X-ray; 2.40 A; A/B=1-295. DR PDB; 4TWC; X-ray; 1.70 A; A/B=1-295. DR PDB; 5IH4; X-ray; 1.90 A; A=1-294. DR PDB; 5IH5; X-ray; 2.25 A; A=1-294. DR PDB; 5IH6; X-ray; 2.30 A; A=1-294. DR PDB; 5MQV; X-ray; 2.15 A; A/B/C/D/E/F=1-294. DR PDB; 5OKT; X-ray; 2.13 A; A/B/C/D=1-294. DR PDB; 5W4W; X-ray; 1.99 A; A/B/C/D=3-317. DR PDB; 6F1W; X-ray; 1.86 A; A/B=1-294. DR PDB; 6F26; X-ray; 1.83 A; A/B=1-294. DR PDB; 6GZM; X-ray; 1.59 A; A/B=1-295. DR PDB; 6HMP; X-ray; 2.04 A; A/B=1-294. DR PDB; 6HMR; X-ray; 1.78 A; A/B=1-294. DR PDB; 6PXN; X-ray; 1.55 A; A/B=1-415. DR PDB; 6PXO; X-ray; 2.00 A; A/B=1-294. DR PDB; 6PXP; X-ray; 2.35 A; A/B=1-294. DR PDB; 6RCG; X-ray; 1.40 A; A=1-294. DR PDB; 6RCH; X-ray; 1.45 A; A/B=1-294. DR PDB; 6RU6; X-ray; 2.05 A; A/B=1-294. DR PDB; 6RU7; X-ray; 2.08 A; A/B=1-294. DR PDB; 6RU8; X-ray; 1.92 A; A/B/C/D=1-294. DR PDB; 7NZY; X-ray; 1.85 A; A/B/C/D=1-294. DR PDB; 7P7F; X-ray; 1.96 A; A/B/C/D=1-294. DR PDB; 7P7G; X-ray; 1.70 A; A/B=1-294. DR PDB; 7P7H; X-ray; 2.40 A; A/B=1-294. DR PDB; 7QR9; X-ray; 2.30 A; A/B/C/D=1-294. DR PDB; 7QRA; X-ray; 2.40 A; A/B/C/D=1-294. DR PDB; 7QRB; X-ray; 2.60 A; A/B/C/D=1-294. DR PDB; 8D7M; X-ray; 2.25 A; A/B=1-294. DR PDB; 8D7N; X-ray; 1.66 A; A/B=1-294. DR PDB; 8D7O; X-ray; 1.65 A; A/B=1-294. DR PDB; 8D7P; X-ray; 2.25 A; A/B=1-294. DR PDB; 8IZC; X-ray; 1.45 A; A/B=5-294. DR PDB; 8VXD; X-ray; 2.47 A; A/B=1-299. DR PDB; 8VXF; X-ray; 2.28 A; A/B=1-299. DR PDB; 9B3S; X-ray; 2.40 A; A/B=1-415. DR PDBsum; 3UYS; -. DR PDBsum; 3UYT; -. DR PDBsum; 3UZP; -. DR PDBsum; 4HGT; -. DR PDBsum; 4HNF; -. DR PDBsum; 4KB8; -. DR PDBsum; 4KBA; -. DR PDBsum; 4KBC; -. DR PDBsum; 4KBK; -. DR PDBsum; 4TN6; -. DR PDBsum; 4TW9; -. DR PDBsum; 4TWC; -. DR PDBsum; 5IH4; -. DR PDBsum; 5IH5; -. DR PDBsum; 5IH6; -. DR PDBsum; 5MQV; -. DR PDBsum; 5OKT; -. DR PDBsum; 5W4W; -. DR PDBsum; 6F1W; -. DR PDBsum; 6F26; -. DR PDBsum; 6GZM; -. DR PDBsum; 6HMP; -. DR PDBsum; 6HMR; -. DR PDBsum; 6PXN; -. DR PDBsum; 6PXO; -. DR PDBsum; 6PXP; -. DR PDBsum; 6RCG; -. DR PDBsum; 6RCH; -. DR PDBsum; 6RU6; -. DR PDBsum; 6RU7; -. DR PDBsum; 6RU8; -. DR PDBsum; 7NZY; -. DR PDBsum; 7P7F; -. DR PDBsum; 7P7G; -. DR PDBsum; 7P7H; -. DR PDBsum; 7QR9; -. DR PDBsum; 7QRA; -. DR PDBsum; 7QRB; -. DR PDBsum; 8D7M; -. DR PDBsum; 8D7N; -. DR PDBsum; 8D7O; -. DR PDBsum; 8D7P; -. DR PDBsum; 8IZC; -. DR PDBsum; 8VXD; -. DR PDBsum; 8VXF; -. DR PDBsum; 9B3S; -. DR AlphaFoldDB; P48730; -. DR SMR; P48730; -. DR BioGRID; 107837; 268. DR DIP; DIP-39735N; -. DR FunCoup; P48730; 4598. DR IntAct; P48730; 204. DR MINT; P48730; -. DR STRING; 9606.ENSP00000381531; -. DR BindingDB; P48730; -. DR ChEMBL; CHEMBL2828; -. DR DrugCentral; P48730; -. DR GuidetoPHARMACOLOGY; 1997; -. DR GlyGen; P48730; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P48730; -. DR PhosphoSitePlus; P48730; -. DR BioMuta; CSNK1D; -. DR DMDM; 27923980; -. DR CPTAC; CPTAC-3148; -. DR CPTAC; CPTAC-3149; -. DR jPOST; P48730; -. DR MassIVE; P48730; -. DR PaxDb; 9606-ENSP00000324464; -. DR PeptideAtlas; P48730; -. DR ProteomicsDB; 55930; -. [P48730-1] DR ProteomicsDB; 55931; -. [P48730-2] DR Pumba; P48730; -. DR TopDownProteomics; P48730-1; -. [P48730-1] DR Antibodypedia; 4210; 368 antibodies from 40 providers. DR DNASU; 1453; -. DR Ensembl; ENST00000314028.11; ENSP00000324464.6; ENSG00000141551.16. [P48730-1] DR Ensembl; ENST00000392334.7; ENSP00000376146.2; ENSG00000141551.16. [P48730-2] DR GeneID; 1453; -. DR KEGG; hsa:1453; -. DR MANE-Select; ENST00000314028.11; ENSP00000324464.6; NM_001893.6; NP_001884.2. DR UCSC; uc002kei.4; human. [P48730-1] DR AGR; HGNC:2452; -. DR ClinPGx; PA26952; -. DR CTD; 1453; -. DR DisGeNET; 1453; -. DR GeneCards; CSNK1D; -. DR HGNC; HGNC:2452; CSNK1D. DR HPA; ENSG00000141551; Low tissue specificity. DR MalaCards; CSNK1D; -. DR MIM; 600864; gene. DR MIM; 615224; phenotype. DR OpenTargets; ENSG00000141551; -. DR Orphanet; 164736; Familial advanced sleep-phase syndrome. DR VEuPathDB; HostDB:ENSG00000141551; -. DR eggNOG; KOG1164; Eukaryota. DR GeneTree; ENSGT00940000153536; -. DR HOGENOM; CLU_019279_2_2_1; -. DR InParanoid; P48730; -. DR OMA; IFDWTFL; -. DR OrthoDB; 5800476at2759; -. DR PAN-GO; P48730; 11 GO annotations based on evolutionary models. DR PhylomeDB; P48730; -. DR BRENDA; 2.7.11.1; 2681. DR BRENDA; 2.7.11.26; 2681. DR PathwayCommons; P48730; -. DR Reactome; R-HSA-204005; COPII-mediated vesicle transport. DR Reactome; R-HSA-2565942; Regulation of PLK1 Activity at G2/M Transition. DR Reactome; R-HSA-380259; Loss of Nlp from mitotic centrosomes. DR Reactome; R-HSA-380270; Recruitment of mitotic centrosome proteins and complexes. DR Reactome; R-HSA-380284; Loss of proteins required for interphase microtubule organization from the centrosome. DR Reactome; R-HSA-380320; Recruitment of NuMA to mitotic centrosomes. DR Reactome; R-HSA-5620912; Anchoring of the basal body to the plasma membrane. DR Reactome; R-HSA-6791226; Major pathway of rRNA processing in the nucleolus and cytosol. DR Reactome; R-HSA-8854518; AURKA Activation by TPX2. DR Reactome; R-HSA-9931521; The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex. DR Reactome; R-HSA-9931530; Phosphorylation and nuclear translocation of the CRY:PER:kinase complex. DR SABIO-RK; P48730; -. DR SignaLink; P48730; -. DR SIGNOR; P48730; -. DR Agora; ENSG00000141551; -. DR BioGRID-ORCS; 1453; 26 hits in 1201 CRISPR screens. DR CD-CODE; 8C2F96ED; Centrosome. DR CD-CODE; 91857CE7; Nucleolus. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; CSNK1D; human. DR EvolutionaryTrace; P48730; -. DR GeneWiki; CSNK1D; -. DR GenomeRNAi; 1453; -. DR Pharos; P48730; Tchem. DR PRO; PR:P48730; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; P48730; protein. DR Bgee; ENSG00000141551; Expressed in left testis and 205 other cell types or tissues. DR ExpressionAtlas; P48730; baseline and differential. DR GO; GO:0015629; C:actin cytoskeleton; IDA:HPA. DR GO; GO:0005813; C:centrosome; IDA:UniProtKB. DR GO; GO:0036064; C:ciliary basal body; IDA:GO_Central. DR GO; GO:0005929; C:cilium; IDA:HPA. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0033116; C:endoplasmic reticulum-Golgi intermediate compartment membrane; TAS:Reactome. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0097229; C:sperm end piece; IDA:HPA. DR GO; GO:0097228; C:sperm principal piece; IDA:HPA. DR GO; GO:0005819; C:spindle; IDA:UniProtKB. DR GO; GO:0005876; C:spindle microtubule; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0045296; F:cadherin binding; HDA:BHF-UCL. DR GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB. DR GO; GO:0106310; F:protein serine kinase activity; IDA:UniProtKB. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0050321; F:tau-protein kinase activity; IDA:UniProtKB. DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB. DR GO; GO:0048208; P:COPII vesicle coating; TAS:Reactome. DR GO; GO:0006897; P:endocytosis; IBA:GO_Central. DR GO; GO:0007030; P:Golgi organization; IMP:SYSCILIA_CCNET. DR GO; GO:0007020; P:microtubule nucleation; IMP:SYSCILIA_CCNET. DR GO; GO:1904948; P:midbrain dopaminergic neuron differentiation; ISS:ParkinsonsUK-UCL. DR GO; GO:1905515; P:non-motile cilium assembly; IMP:SYSCILIA_CCNET. DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; IMP:BHF-UCL. DR GO; GO:2000052; P:positive regulation of non-canonical Wnt signaling pathway; ISS:ParkinsonsUK-UCL. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; ISS:UniProtKB. DR GO; GO:0071539; P:protein localization to centrosome; IMP:SYSCILIA_CCNET. DR GO; GO:0061512; P:protein localization to cilium; IMP:SYSCILIA_CCNET. DR GO; GO:0034067; P:protein localization to Golgi apparatus; IMP:SYSCILIA_CCNET. DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB. DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB. DR GO; GO:0007165; P:signal transduction; IBA:GO_Central. DR GO; GO:0051225; P:spindle assembly; IDA:UniProtKB. DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW. DR CDD; cd14125; STKc_CK1_delta_epsilon; 1. DR FunFam; 1.10.510.10:FF:000194; Casein kinase I isoform delta; 1. DR FunFam; 3.30.200.20:FF:000538; Putative Casein kinase I; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR050235; CK1_Ser-Thr_kinase. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR11909; CASEIN KINASE-RELATED; 1. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Biological rhythms; KW Cell membrane; Cytoplasm; Cytoskeleton; Disease variant; Golgi apparatus; KW Kinase; Membrane; Methylation; Nucleotide-binding; Nucleus; Phosphoprotein; KW Proteomics identification; Reference proteome; KW Serine/threonine-protein kinase; Transferase; Wnt signaling pathway. FT CHAIN 1..415 FT /note="Casein kinase I isoform delta" FT /id="PRO_0000192833" FT DOMAIN 9..277 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REGION 278..364 FT /note="Centrosomal localization signal (CLS)" FT REGION 301..415 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 317..342 FT /note="Autoinhibitory" FT /evidence="ECO:0000250" FT COMPBIAS 301..315 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 347..358 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 380..400 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 128 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 15..23 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 38 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT MOD_RES 328 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 331 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 370 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q06486" FT MOD_RES 375 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0000250|UniProtKB:Q9DC28" FT MOD_RES 382 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 383 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 384 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 407 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 411 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19369195" FT VAR_SEQ 400..415 FT /note="IPGRVASSGLQSVVHR -> NSIPFEHHGK (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334" FT /id="VSP_010253" FT VARIANT 44 FT /note="T -> A (in FASPS2; strongly reduces kinase activity; FT dbSNP:rs104894561)" FT /evidence="ECO:0000269|PubMed:15800623, FT ECO:0000269|PubMed:23636092" FT /id="VAR_029075" FT VARIANT 46 FT /note="H -> R (in FASPS2; strongly reduces kinase activity; FT dbSNP:rs397514693)" FT /evidence="ECO:0000269|PubMed:23636092" FT /id="VAR_069801" FT VARIANT 97 FT /note="S -> C (in breast cancer samples; infiltrating FT ductal carcinoma; somatic mutation)" FT /evidence="ECO:0000269|PubMed:16959974, FT ECO:0000269|PubMed:17344846" FT /id="VAR_036451" FT VARIANT 401 FT /note="P -> A (in dbSNP:rs56124628)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042081" FT MUTAGEN 38 FT /note="K->M: Impaired kinase activity and abnormal FT subcellular localization with exclusive accumulation to the FT nucleus." FT /evidence="ECO:0000269|PubMed:11161704" FT MUTAGEN 176 FT /note="T->I: Impaired kinase activity and abnormal FT subcellular localization with exclusive accumulation to the FT nucleus." FT /evidence="ECO:0000269|PubMed:11161704" FT CONFLICT 330 FT /note="A -> D (in Ref. 1; AAC50807)" FT /evidence="ECO:0000305" FT STRAND 3..5 FT /evidence="ECO:0007829|PDB:6RCG" FT TURN 6..8 FT /evidence="ECO:0007829|PDB:6RCG" FT STRAND 9..18 FT /evidence="ECO:0007829|PDB:6RCG" FT STRAND 21..28 FT /evidence="ECO:0007829|PDB:6RCG" FT TURN 29..32 FT /evidence="ECO:0007829|PDB:6RCG" FT STRAND 33..41 FT /evidence="ECO:0007829|PDB:6RCG" FT STRAND 44..46 FT /evidence="ECO:0007829|PDB:6RCG" FT HELIX 49..59 FT /evidence="ECO:0007829|PDB:6RCG" FT STRAND 68..74 FT /evidence="ECO:0007829|PDB:6RCG" FT STRAND 77..83 FT /evidence="ECO:0007829|PDB:6RCG" FT HELIX 89..95 FT /evidence="ECO:0007829|PDB:6RCG" FT TURN 96..98 FT /evidence="ECO:0007829|PDB:6RCG" FT HELIX 102..121 FT /evidence="ECO:0007829|PDB:6RCG" FT HELIX 131..133 FT /evidence="ECO:0007829|PDB:6RCG" FT STRAND 134..136 FT /evidence="ECO:0007829|PDB:6RCG" FT HELIX 139..141 FT /evidence="ECO:0007829|PDB:6RCG" FT STRAND 145..147 FT /evidence="ECO:0007829|PDB:6RCG" FT STRAND 154..157 FT /evidence="ECO:0007829|PDB:8D7O" FT TURN 159..161 FT /evidence="ECO:0007829|PDB:6RCG" FT HELIX 177..179 FT /evidence="ECO:0007829|PDB:6RCG" FT HELIX 182..185 FT /evidence="ECO:0007829|PDB:6RCG" FT HELIX 192..208 FT /evidence="ECO:0007829|PDB:6RCG" FT TURN 212..215 FT /evidence="ECO:0007829|PDB:6RCH" FT STRAND 217..219 FT /evidence="ECO:0007829|PDB:6RCG" FT HELIX 221..233 FT /evidence="ECO:0007829|PDB:6RCG" FT HELIX 237..240 FT /evidence="ECO:0007829|PDB:6RCG" FT TURN 241..243 FT /evidence="ECO:0007829|PDB:6RCG" FT HELIX 247..257 FT /evidence="ECO:0007829|PDB:6RCG" FT HELIX 266..279 FT /evidence="ECO:0007829|PDB:6RCG" FT HELIX 280..283 FT /evidence="ECO:0007829|PDB:6F1W" FT HELIX 289..292 FT /evidence="ECO:0007829|PDB:6RCG" SQ SEQUENCE 415 AA; 47330 MW; B97F1717A52466D2 CRC64; MELRVGNRYR LGRKIGSGSF GDIYLGTDIA AGEEVAIKLE CVKTKHPQLH IESKIYKMMQ GGVGIPTIRW CGAEGDYNVM VMELLGPSLE DLFNFCSRKF SLKTVLLLAD QMISRIEYIH SKNFIHRDVK PDNFLMGLGK KGNLVYIIDF GLAKKYRDAR THQHIPYREN KNLTGTARYA SINTHLGIEQ SRRDDLESLG YVLMYFNLGS LPWQGLKAAT KRQKYERISE KKMSTPIEVL CKGYPSEFAT YLNFCRSLRF DDKPDYSYLR QLFRNLFHRQ GFSYDYVFDW NMLKFGASRA ADDAERERRD REERLRHSRN PATRGLPSTA SGRLRGTQEV APPTPLTPTS HTANTSPRPV SGMERERKVS MRLHRGAPVN ISSSDLTGRQ DTSRMSTSQI PGRVASSGLQ SVVHR // ID KLK8_HUMAN Reviewed; 260 AA. AC O60259; Q5V9X1; Q5V9X2; Q8IW69; Q9HCB3; Q9NR68; Q9NR69; Q9UIL9; Q9UQ47; DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot. DT 01-AUG-1998, sequence version 1. DT 28-JAN-2026, entry version 204. DE RecName: Full=Kallikrein-8; DE Short=hK8; DE EC=3.4.21.118; DE AltName: Full=Neuropsin; DE Short=NP; DE AltName: Full=Ovasin; DE AltName: Full=Serine protease 19; DE AltName: Full=Serine protease TADG-14; DE AltName: Full=Tumor-associated differentially expressed gene 14 protein; DE Flags: Precursor; GN Name=KLK8; Synonyms=NRPN, PRSS19, TADG14; ORFNames=UNQ283/PRO322; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1). RC TISSUE=Hippocampus; RX PubMed=9714609; DOI=10.1016/s0378-1119(98)00232-7; RA Yoshida S., Taniguchi M., Hirata A., Shiosaka S.; RT "Sequence analysis and expression of human neuropsin cDNA and gene."; RL Gene 213:9-16(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Ovary; RX PubMed=10485494; RA Underwood L.J., Tanimoto H., Wang Y., Shigemasa K., Parmley T.H., RA O'Brien T.J.; RT "Cloning of tumor-associated differentially expressed gene-14, a novel RT serine protease overexpressed by ovarian carcinoma."; RL Cancer Res. 59:4435-4439(1999). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Brain; RX PubMed=10102990; DOI=10.1046/j.1432-1327.1999.00213.x; RA Mitsui S., Tsuruoka N., Yamashiro K., Nakazato H., Yamaguchi N.; RT "A novel form of human neuropsin, a brain-related serine protease, is RT generated by alternative splicing and is expressed preferentially in human RT adult brain."; RL Eur. J. Biochem. 260:627-634(1999). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=11054574; DOI=10.1016/s0378-1119(00)00382-6; RA Gan L., Lee I., Smith R., Argonza-Barrett R., Lei H., McCuaig J., Moss P., RA Paeper B., Wang K.; RT "Sequencing and expression analysis of the serine protease gene cluster RT located in chromosome 19q13 region."; RL Gene 257:119-130(2000). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 3 AND 4), AND TISSUE RP SPECIFICITY. RX PubMed=11309326; RA Magklara A., Scorilas A., Katsaros D., Massobrio M., Yousef G.M., RA Fracchioli S., Danese S., Diamandis E.P.; RT "The human KLK8 (neuropsin/ovasin) gene: identification of two novel splice RT variants and its prognostic value in ovarian cancer."; RL Clin. Cancer Res. 7:806-811(2001). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1). RA Gan L., Gelinas R., Gown A.M., Moss P., Smith R., Wang K.; RT "Molecular cloning and characterization of a novel serine protease, ovasin, RT a potential molecular marker for ovarian carcinomas."; RL Submitted (SEP-1998) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3). RA Michael I.P., Diamandis E.P.; RT "Human kallikrein 8 and human kallikrein 9 are organized as a bicistronic RT operon."; RL Submitted (OCT-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RX PubMed=12975309; DOI=10.1101/gr.1293003; RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A., RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.; RT "The secreted protein discovery initiative (SPDI), a large-scale effort to RT identify novel human secreted and transmembrane proteins: a bioinformatics RT assessment."; RL Genome Res. 13:2265-2270(2003). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057824; DOI=10.1038/nature02399; RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A., RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., RA Rubin E.M., Lucas S.M.; RT "The DNA sequence and biology of human chromosome 19."; RL Nature 428:529-535(2004). RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [12] RP PARTIAL NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1 AND 2). RX PubMed=15282331; DOI=10.1093/molbev/msh220; RA Li Y., Qian Y.-P., Yu X.-J., Wang Y.-Q., Dong D.-G., Sun W., Ma R.-M., RA Su B.; RT "Recent origin of a hominoid-specific splice form of neuropsin, a gene RT involved in learning and memory."; RL Mol. Biol. Evol. 21:2111-2115(2004). RN [13] RP TISSUE SPECIFICITY. RX PubMed=11522960; DOI=10.1097/00001756-200108280-00031; RA Shimizu-Okabe C., Yousef G.M., Diamandis E.P., Yoshida S., Shiosaka S., RA Fahnestock M.; RT "Expression of the kallikrein gene family in normal and Alzheimer's disease RT brain."; RL NeuroReport 12:2747-2751(2001). RN [14] RP TISSUE SPECIFICITY. RX PubMed=12147714; DOI=10.1136/mp.55.4.235; RA Kuwae K., Matsumoto-Miyai K., Yoshida S., Sadayama T., Yoshikawa K., RA Hosokawa K., Shiosaka S.; RT "Epidermal expression of serine protease, neuropsin (KLK8) in normal and RT pathological skin samples."; RL Mol. Pathol. 55:235-241(2002). RN [15] RP USE AS A MARKER FOR OVARIAN CANCER. RX PubMed=12782581; RA Kishi T., Grass L., Soosaipillai A., Scorilas A., Harbeck N., RA Schmalfeldt B., Dorn J., Mysliwiec M., Schmitt M., Diamandis E.P.; RT "Human kallikrein 8, a novel biomarker for ovarian carcinoma."; RL Cancer Res. 63:2771-2774(2003). RN [16] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND BIOPHYSICOCHEMICAL RP PROPERTIES. RX PubMed=16337200; DOI=10.1016/j.febslet.2005.11.039; RA Rajapakse S., Ogiwara K., Takano N., Moriyama A., Takahashi T.; RT "Biochemical characterization of human kallikrein 8 and its possible RT involvement in the degradation of extracellular matrix proteins."; RL FEBS Lett. 579:6879-6884(2005). RN [17] RP ALTERNATIVE SPLICING (ISOFORM 2). RX PubMed=17487847; DOI=10.1002/humu.20547; RA Lu Z.-X., Peng J., Su B.; RT "A human-specific mutation leads to the origin of a novel splice form of RT neuropsin (KLK8), a gene involved in learning and memory."; RL Hum. Mutat. 28:978-984(2007). RN [18] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=17761692; DOI=10.1093/jb/mvm156; RA Scott F.L., Sun J., Whisstock J.C., Kato K., Bird P.I.; RT "SerpinB6 is an inhibitor of kallikrein-8 in keratinocytes."; RL J. Biochem. 142:435-442(2007). RN [19] RP INTERACTION WITH SPINK9. RX PubMed=19194479; DOI=10.1038/jid.2008.448; RA Brattsand M., Stefansson K., Hubiche T., Nilsson S.K., Egelrud T.; RT "SPINK9: a selective, skin-specific Kazal-type serine protease inhibitor."; RL J. Invest. Dermatol. 129:1656-1665(2009). CC -!- FUNCTION: Serine protease which is capable of degrading a number of CC proteins such as casein, fibrinogen, kininogen, fibronectin and CC collagen type IV. Also cleaves L1CAM in response to increased neural CC activity. Induces neurite outgrowth and fasciculation of cultured CC hippocampal neurons. Plays a role in the formation and maturation of CC orphan and small synaptic boutons in the Schaffer-collateral pathway, CC regulates Schaffer-collateral long-term potentiation in the hippocampus CC and is required for memory acquisition and synaptic plasticity. CC Involved in skin desquamation and keratinocyte proliferation. Plays a CC role in the secondary phase of pathogenesis following spinal cord CC injury. {ECO:0000269|PubMed:16337200}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Cleavage of amide substrates following the basic amino acids CC Arg or Lys at the P1 position, with a preference for Arg over Lys.; CC EC=3.4.21.118; Evidence={ECO:0000269|PubMed:16337200}; CC -!- ACTIVITY REGULATION: Inhibited by a range of serine protease inhibitors CC including antipain, aprotinin, leupeptin, benzamidine and soybean CC trypsin inhibitor. {ECO:0000269|PubMed:16337200}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=0.07 mM for Pro-Phe-Arg-MCA {ECO:0000269|PubMed:16337200}; CC KM=0.07 mM for Z-Val-Val-Arg-MCA {ECO:0000269|PubMed:16337200}; CC KM=0.07 mM for Boc-Val-Pro-Arg-MCA {ECO:0000269|PubMed:16337200}; CC KM=0.10 mM for Boc-Leu-Lys-Arg-MCA {ECO:0000269|PubMed:16337200}; CC KM=0.10 mM for Boc-Val-Leu-Lys-MCA {ECO:0000269|PubMed:16337200}; CC KM=0.07 mM for Boc-Phe-Ser-Arg-MCA {ECO:0000269|PubMed:16337200}; CC Vmax=7.1 umol/min/mg enzyme toward Pro-Phe-Arg-MCA CC {ECO:0000269|PubMed:16337200}; CC Vmax=5.4 umol/min/mg enzyme toward Z-Val-Val-Arg-MCA CC {ECO:0000269|PubMed:16337200}; CC Vmax=3.9 umol/min/mg enzyme toward Boc-Val-Pro-Arg-MCA CC {ECO:0000269|PubMed:16337200}; CC Vmax=2.6 umol/min/mg enzyme toward Boc-Leu-Lys-Arg-MCA CC {ECO:0000269|PubMed:16337200}; CC Vmax=1.9 umol/min/mg enzyme toward Boc-Val-Leu-Lys-MCA CC {ECO:0000269|PubMed:16337200}; CC Vmax=1.6 umol/min/mg enzyme toward Boc-Phe-Ser-Arg-MCA CC {ECO:0000269|PubMed:16337200}; CC pH dependence: CC Optimum pH is 8.5. Active from pH 7-10. CC {ECO:0000269|PubMed:16337200}; CC -!- SUBUNIT: Interacts with SPINK9. {ECO:0000269|PubMed:19194479}. CC -!- INTERACTION: CC O60259; A8MQ03: CYSRT1; NbExp=3; IntAct=EBI-3915857, EBI-3867333; CC O60259; P42858: HTT; NbExp=3; IntAct=EBI-3915857, EBI-466029; CC O60259; Q92876: KLK6; NbExp=3; IntAct=EBI-3915857, EBI-2432309; CC O60259; Q15323: KRT31; NbExp=3; IntAct=EBI-3915857, EBI-948001; CC O60259; O76011: KRT34; NbExp=3; IntAct=EBI-3915857, EBI-1047093; CC O60259; Q07627: KRTAP1-1; NbExp=3; IntAct=EBI-3915857, EBI-11959885; CC O60259; P60410: KRTAP10-8; NbExp=3; IntAct=EBI-3915857, EBI-10171774; CC O60259; P26371: KRTAP5-9; NbExp=3; IntAct=EBI-3915857, EBI-3958099; CC O60259; Q7Z3S9: NOTCH2NLA; NbExp=3; IntAct=EBI-3915857, EBI-945833; CC O60259; P0DPK4: NOTCH2NLC; NbExp=3; IntAct=EBI-3915857, EBI-22310682; CC O60259; P50454: SERPINH1; NbExp=3; IntAct=EBI-3915857, EBI-350723; CC O60259; P37173: TGFBR2; NbExp=3; IntAct=EBI-3915857, EBI-296151; CC O60259; Q8IUH5: ZDHHC17; NbExp=3; IntAct=EBI-3915857, EBI-524753; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:17761692}. Cytoplasm CC {ECO:0000269|PubMed:17761692}. Note=Shows a cytoplasmic distribution in CC the keratinocytes. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; CC IsoId=O60259-1; Sequence=Displayed; CC Name=2; CC IsoId=O60259-2; Sequence=VSP_005401; CC Name=3; CC IsoId=O60259-3; Sequence=VSP_030350; CC Name=4; CC IsoId=O60259-4; Sequence=VSP_030351, VSP_030352; CC -!- TISSUE SPECIFICITY: Isoform 1 is predominantly expressed in the CC pancreas. Isoform 2 is expressed in adult brain and hippocampus. CC Isoform 1 and isoform 2 are found in fetal brain and placenta. Detected CC in salivary gland, uterus, thymus, breast, testis and kidney but not in CC spleen, liver, lung or normal ovarian tissue. Displays an 11.5-fold CC increase in Alzheimer disease hippocampus compared to controls and is CC overexpressed in some ovarian carcinomas. Expressed at low levels in CC normal skin while high levels are found in psoriasis vulgaris, CC seborrheic keratosis, lichen planus and squamous cell carcinoma skin CC samples. Expressed in the keratinocytes. {ECO:0000269|PubMed:11309326, CC ECO:0000269|PubMed:11522960, ECO:0000269|PubMed:12147714, CC ECO:0000269|PubMed:17761692}. CC -!- MISCELLANEOUS: Expressed at high levels in serum, ascites fluid and CC tumor cytosol of advanced stage ovarian cancer patients and may serve CC as a marker of ovarian cancer. CC -!- MISCELLANEOUS: [Isoform 2]: Produced as a result of a human-specific CC mutation which is not found in other primates. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the peptidase S1 family. Kallikrein subfamily. CC {ECO:0000255|PROSITE-ProRule:PRU00274}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/41088/KLK8"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AB009849; BAA28673.1; -; mRNA. DR EMBL; AB012761; BAA28676.1; -; Genomic_DNA. DR EMBL; AF055982; AAD56050.1; -; mRNA. DR EMBL; AB008390; BAA82665.1; -; mRNA. DR EMBL; AB008927; BAA82666.1; -; mRNA. DR EMBL; AB010780; BAA88684.1; -; Genomic_DNA. DR EMBL; AF243527; AAG33361.1; -; Genomic_DNA. DR EMBL; AF251125; AAF79144.1; -; Genomic_DNA. DR EMBL; AF251125; AAF79145.1; -; Genomic_DNA. DR EMBL; AF095742; AAD25979.1; -; mRNA. DR EMBL; AF095743; AAD29574.1; -; Genomic_DNA. DR EMBL; DQ267420; ABB83339.1; -; mRNA. DR EMBL; AY359036; AAQ89395.1; -; mRNA. DR EMBL; AC011473; AAG23254.1; -; Genomic_DNA. DR EMBL; AC011483; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471135; EAW71962.1; -; Genomic_DNA. DR EMBL; BC040887; AAH40887.1; -; mRNA. DR EMBL; AY563055; AAT76913.1; -; Genomic_DNA. DR EMBL; AY563055; AAT76914.1; -; Genomic_DNA. DR EMBL; AY563056; AAT76915.1; -; Genomic_DNA. DR EMBL; AY563056; AAT76916.1; -; Genomic_DNA. DR EMBL; AY563057; AAT76917.1; -; Genomic_DNA. DR EMBL; AY563057; AAT76918.1; -; Genomic_DNA. DR EMBL; AY563058; AAT76919.1; -; Genomic_DNA. DR EMBL; AY563058; AAT76920.1; -; Genomic_DNA. DR EMBL; AY563059; AAT76921.1; -; Genomic_DNA. DR EMBL; AY563059; AAT76922.1; -; Genomic_DNA. DR EMBL; AY563060; AAT76923.1; -; Genomic_DNA. DR EMBL; AY563060; AAT76924.1; -; Genomic_DNA. DR EMBL; AY563061; AAT76925.1; -; Genomic_DNA. DR EMBL; AY563061; AAT76926.1; -; Genomic_DNA. DR EMBL; AY563062; AAT76927.1; -; Genomic_DNA. DR EMBL; AY563062; AAT76928.1; -; Genomic_DNA. DR EMBL; AY563063; AAT76929.1; -; Genomic_DNA. DR EMBL; AY563063; AAT76930.1; -; Genomic_DNA. DR EMBL; AY563064; AAT76931.1; -; Genomic_DNA. DR EMBL; AY563064; AAT76932.1; -; Genomic_DNA. DR EMBL; AY563065; AAT76933.1; -; Genomic_DNA. DR EMBL; AY563065; AAT76934.1; -; Genomic_DNA. DR EMBL; AY563066; AAT76935.1; -; Genomic_DNA. DR EMBL; AY563066; AAT76936.1; -; Genomic_DNA. DR EMBL; AY563067; AAT76937.1; -; Genomic_DNA. DR EMBL; AY563067; AAT76938.1; -; Genomic_DNA. DR CCDS; CCDS12813.1; -. [O60259-1] DR CCDS; CCDS12814.1; -. [O60259-3] DR CCDS; CCDS12815.1; -. [O60259-4] DR CCDS; CCDS42600.1; -. [O60259-2] DR RefSeq; NP_001268360.1; NM_001281431.1. DR RefSeq; NP_009127.1; NM_007196.4. [O60259-1] DR RefSeq; NP_653088.1; NM_144505.3. [O60259-2] DR RefSeq; NP_653089.1; NM_144506.3. [O60259-3] DR RefSeq; NP_653090.1; NM_144507.3. [O60259-4] DR PDB; 5MS3; X-ray; 2.30 A; A=33-260. DR PDB; 5MS4; X-ray; 2.10 A; A/B/C/D=33-260. DR PDBsum; 5MS3; -. DR PDBsum; 5MS4; -. DR AlphaFoldDB; O60259; -. DR SMR; O60259; -. DR BioGRID; 116371; 46. DR FunCoup; O60259; 73. DR IntAct; O60259; 33. DR STRING; 9606.ENSP00000375682; -. DR BindingDB; O60259; -. DR ChEMBL; CHEMBL4812; -. DR GuidetoPHARMACOLOGY; 2378; -. DR MEROPS; S01.244; -. DR GlyCosmos; O60259; 1 site, No reported glycans. DR GlyGen; O60259; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; O60259; -. DR PhosphoSitePlus; O60259; -. DR BioMuta; KLK8; -. DR jPOST; O60259; -. DR MassIVE; O60259; -. DR PeptideAtlas; O60259; -. DR ProteomicsDB; 49286; -. [O60259-1] DR ProteomicsDB; 49287; -. [O60259-2] DR ProteomicsDB; 49288; -. [O60259-3] DR Pumba; O60259; -. DR Antibodypedia; 32417; 1348 antibodies from 32 providers. DR DNASU; 11202; -. DR Ensembl; ENST00000320838.9; ENSP00000325072.5; ENSG00000129455.17. [O60259-4] DR Ensembl; ENST00000347619.8; ENSP00000341555.3; ENSG00000129455.17. [O60259-3] DR Ensembl; ENST00000391806.6; ENSP00000375682.1; ENSG00000129455.17. [O60259-2] DR Ensembl; ENST00000593490.1; ENSP00000469278.1; ENSG00000129455.17. [O60259-4] DR Ensembl; ENST00000600767.5; ENSP00000472016.1; ENSG00000129455.17. [O60259-1] DR Ensembl; ENST00000695909.1; ENSP00000512260.1; ENSG00000129455.17. [O60259-1] DR GeneID; 11202; -. DR KEGG; hsa:11202; -. DR MANE-Select; ENST00000695909.1; ENSP00000512260.1; NM_007196.4; NP_009127.1. DR UCSC; uc002puq.2; human. [O60259-1] DR AGR; HGNC:6369; -. DR ClinPGx; PA30158; -. DR CTD; 11202; -. DR DisGeNET; 11202; -. DR GeneCards; KLK8; -. DR HGNC; HGNC:6369; KLK8. DR HPA; ENSG00000129455; Tissue enhanced (esophagus, skin, vagina). DR MIM; 605644; gene. DR OpenTargets; ENSG00000129455; -. DR VEuPathDB; HostDB:ENSG00000129455; -. DR GeneTree; ENSGT01020000230389; -. DR HOGENOM; CLU_006842_1_1_1; -. DR InParanoid; O60259; -. DR OMA; GMTCYSG; -. DR OrthoDB; 546450at2759; -. DR PAN-GO; O60259; 3 GO annotations based on evolutionary models. DR PhylomeDB; O60259; -. DR BRENDA; 3.4.21.118; 2681. DR PathwayCommons; O60259; -. DR Reactome; R-HSA-6809371; Formation of the cornified envelope. DR SignaLink; O60259; -. DR Agora; ENSG00000129455; -. DR BioGRID-ORCS; 11202; 10 hits in 1144 CRISPR screens. DR GeneWiki; KLK8; -. DR GenomeRNAi; 11202; -. DR Pharos; O60259; Tchem. DR PRO; PR:O60259; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; O60259; protein. DR Bgee; ENSG00000129455; Expressed in lower esophagus mucosa and 104 other cell types or tissues. DR ExpressionAtlas; O60259; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; ISS:UniProtKB. DR GO; GO:0030141; C:secretory granule; IBA:GO_Central. DR GO; GO:0097180; C:serine protease inhibitor complex; IDA:BHF-UCL. DR GO; GO:0004252; F:serine-type endopeptidase activity; IDA:UniProtKB. DR GO; GO:0038130; P:ERBB4 signaling pathway; IEA:Ensembl. DR GO; GO:0043616; P:keratinocyte proliferation; ISS:UniProtKB. DR GO; GO:0007613; P:memory; ISS:UniProtKB. DR GO; GO:0048812; P:neuron projection morphogenesis; ISS:UniProtKB. DR GO; GO:0051604; P:protein maturation; IBA:GO_Central. DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW. DR GO; GO:0050807; P:regulation of synapse organization; ISS:UniProtKB. DR GO; GO:0009611; P:response to wounding; ISS:UniProtKB. DR GO; GO:0050808; P:synapse organization; IEA:Ensembl. DR CDD; cd00190; Tryp_SPc; 1. DR FunFam; 2.40.10.10:FF:000087; Kallikrein 8 (Neuropsin/ovasin); 1. DR FunFam; 2.40.10.10:FF:000041; kallikrein-6 isoform X2; 1. DR Gene3D; 2.40.10.10; Trypsin-like serine proteases; 2. DR InterPro; IPR009003; Peptidase_S1_PA. DR InterPro; IPR043504; Peptidase_S1_PA_chymotrypsin. DR InterPro; IPR001314; Peptidase_S1A. DR InterPro; IPR001254; Trypsin_dom. DR InterPro; IPR018114; TRYPSIN_HIS. DR InterPro; IPR033116; TRYPSIN_SER. DR PANTHER; PTHR24271:SF62; KALLIKREIN-8; 1. DR PANTHER; PTHR24271; KALLIKREIN-RELATED; 1. DR Pfam; PF00089; Trypsin; 1. DR PRINTS; PR00722; CHYMOTRYPSIN. DR SMART; SM00020; Tryp_SPc; 1. DR SUPFAM; SSF50494; Trypsin-like serine proteases; 1. DR PROSITE; PS50240; TRYPSIN_DOM; 1. DR PROSITE; PS00134; TRYPSIN_HIS; 1. DR PROSITE; PS00135; TRYPSIN_SER; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasm; Disulfide bond; KW Glycoprotein; Hydrolase; Protease; Proteomics identification; KW Reference proteome; Secreted; Serine protease; Signal; Zymogen. FT SIGNAL 1..28 FT /evidence="ECO:0000255" FT PROPEP 29..32 FT /evidence="ECO:0000250" FT /id="PRO_0000027946" FT CHAIN 33..260 FT /note="Kallikrein-8" FT /id="PRO_0000027947" FT DOMAIN 33..257 FT /note="Peptidase S1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274" FT ACT_SITE 73 FT /note="Charge relay system" FT /evidence="ECO:0000250" FT ACT_SITE 120 FT /note="Charge relay system" FT /evidence="ECO:0000250" FT ACT_SITE 212 FT /note="Charge relay system" FT /evidence="ECO:0000250" FT CARBOHYD 110 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 39..173 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274" FT DISULFID 58..74 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274" FT DISULFID 145..246 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274" FT DISULFID 152..218 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274" FT DISULFID 184..198 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274" FT DISULFID 208..233 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274" FT VAR_SEQ 23 FT /note="A -> AACGSLDLLTKLYAENLPCVHLNPQWPSQPSHCPRGWRSNPLPPAA FT (in isoform 2)" FT /evidence="ECO:0000303|PubMed:10102990" FT /id="VSP_005401" FT VAR_SEQ 24..164 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|Ref.7" FT /id="VSP_030350" FT VAR_SEQ 25..32 FT /note="HSRAQEDK -> RFWRPPGV (in isoform 4)" FT /evidence="ECO:0000305" FT /id="VSP_030351" FT VAR_SEQ 33..260 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000305" FT /id="VSP_030352" FT VARIANT 154 FT /note="V -> I (in dbSNP:rs16988799)" FT /id="VAR_051855" FT CONFLICT 195 FT /note="G -> V (in Ref. 11; AAH40887)" FT /evidence="ECO:0000305" FT STRAND 47..54 FT /evidence="ECO:0007829|PDB:5MS4" FT STRAND 56..64 FT /evidence="ECO:0007829|PDB:5MS4" FT STRAND 67..70 FT /evidence="ECO:0007829|PDB:5MS4" FT HELIX 72..74 FT /evidence="ECO:0007829|PDB:5MS4" FT STRAND 80..84 FT /evidence="ECO:0007829|PDB:5MS4" FT STRAND 86..90 FT /evidence="ECO:0007829|PDB:5MS4" FT STRAND 96..105 FT /evidence="ECO:0007829|PDB:5MS4" FT STRAND 111..113 FT /evidence="ECO:0007829|PDB:5MS3" FT STRAND 122..128 FT /evidence="ECO:0007829|PDB:5MS4" FT STRAND 133..136 FT /evidence="ECO:0007829|PDB:5MS4" FT STRAND 151..158 FT /evidence="ECO:0007829|PDB:5MS4" FT STRAND 160..164 FT /evidence="ECO:0007829|PDB:5MS4" FT STRAND 172..178 FT /evidence="ECO:0007829|PDB:5MS4" FT HELIX 181..187 FT /evidence="ECO:0007829|PDB:5MS4" FT TURN 189..191 FT /evidence="ECO:0007829|PDB:5MS4" FT STRAND 196..200 FT /evidence="ECO:0007829|PDB:5MS4" FT STRAND 215..228 FT /evidence="ECO:0007829|PDB:5MS4" FT STRAND 231..234 FT /evidence="ECO:0007829|PDB:5MS3" FT STRAND 236..238 FT /evidence="ECO:0007829|PDB:5MS4" FT STRAND 240..244 FT /evidence="ECO:0007829|PDB:5MS4" FT HELIX 245..247 FT /evidence="ECO:0007829|PDB:5MS4" FT HELIX 249..257 FT /evidence="ECO:0007829|PDB:5MS4" SQ SEQUENCE 260 AA; 28048 MW; EF439E5B8C83E660 CRC64; MGRPRPRAAK TWMFLLLLGG AWAGHSRAQE DKVLGGHECQ PHSQPWQAAL FQGQQLLCGG VLVGGNWVLT AAHCKKPKYT VRLGDHSLQN KDGPEQEIPV VQSIPHPCYN SSDVEDHNHD LMLLQLRDQA SLGSKVKPIS LADHCTQPGQ KCTVSGWGTV TSPRENFPDT LNCAEVKIFP QKKCEDAYPG QITDGMVCAG SSKGADTCQG DSGGPLVCDG ALQGITSWGS DPCGRSDKPG VYTNICRYLD WIKKIIGSKG // ID OXDD_HUMAN Reviewed; 341 AA. AC Q99489; A8KAG4; Q5JXM4; Q5JXM5; Q5JXM6; Q8N552; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1997, sequence version 1. DT 28-JAN-2026, entry version 200. DE RecName: Full=D-aspartate oxidase; DE Short=DASOX; DE Short=DASPO {ECO:0000303|PubMed:31914658}; DE Short=DDO; DE EC=1.4.3.1 {ECO:0000269|PubMed:20603179, ECO:0000269|PubMed:25747990, ECO:0000269|PubMed:28393897, ECO:0000269|PubMed:28560262, ECO:0000269|PubMed:29292239, ECO:0000269|PubMed:33650155, ECO:0000269|PubMed:9163533}; GN Name=DDO; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS DDO-1 AND DDO-2), FUNCTION, CATALYTIC RP ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RC TISSUE=Brain; RX PubMed=9163533; DOI=10.1093/oxfordjournals.jbchem.a021655; RA Setoyama C., Miura R.; RT "Structural and functional characterization of the human brain D-aspartate RT oxidase."; RL J. Biochem. 121:798-803(1997). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Uterus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-206 (ISOFORM 4). RA Birkett C., Cho J., Gau Y., Hamer R., Kelly S., Kovacs K., Liu L., Liu X., RA Porter J., Sachs A., Shu Y., Sun Z., Wong J., Wu M., Zhang X., Jay G., RA He W.; RT "High-throughput cloning of full-length human cDNAs directly from cDNA RT libraries optimized for large and rare transcripts."; RL Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=1991137; DOI=10.1016/0304-4165(91)90203-s; RA Van Veldhoven P.P., Brees C., Mannaerts G.P.; RT "D-aspartate oxidase, a peroxisomal enzyme in liver of rat and man."; RL Biochim. Biophys. Acta 1073:203-208(1991). RN [8] RP INTERACTION WITH PEX5, AND MOTIF. RX PubMed=9820813; DOI=10.1042/bj3360367; RA Amery L., Brees C., Baes M., Setoyama C., Miura R., Mannaerts G.P., RA Van Veldhoven P.P.; RT "C-terminal tripeptide Ser-Asn-Leu (SNL) of human D-aspartate oxidase is a RT functional peroxisome-targeting signal."; RL Biochem. J. 336:367-371(1998). RN [9] RP TISSUE SPECIFICITY. RX PubMed=12209855; DOI=10.1002/cne.10320; RA Zaar K., Koest H.P., Schad A., Voelkl A., Baumgart E., Fahimi H.D.; RT "Cellular and subcellular distribution of D-aspartate oxidase in human and RT rat brain."; RL J. Comp. Neurol. 450:272-282(2002). RN [10] RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, AND ACTIVITY REGULATION. RX PubMed=20603179; DOI=10.1016/j.biochi.2010.06.021; RA Katane M., Saitoh Y., Hanai T., Sekine M., Furuchi T., Koyama N., RA Nakagome I., Tomoda H., Hirono S., Homma H.; RT "Thiolactomycin inhibits D-aspartate oxidase: a novel approach to probing RT the active site environment."; RL Biochimie 92:1371-1378(2010). RN [11] RP FUNCTION, CATALYTIC ACTIVITY, AND ACTIVITY REGULATION. RX PubMed=23391306; DOI=10.1021/jm3017865; RA Katane M., Osaka N., Matsuda S., Maeda K., Kawata T., Saitoh Y., Sekine M., RA Furuchi T., Doi I., Hirono S., Homma H.; RT "Identification of novel D-amino acid oxidase inhibitors by in silico RT screening and their functional characterization in vitro."; RL J. Med. Chem. 56:1894-1907(2013). RN [12] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND BIOPHYSICOCHEMICAL RP PROPERTIES. RX PubMed=25747990; DOI=10.1248/bpb.b14-00690; RA Katane M., Kawata T., Nakayama K., Saitoh Y., Kaneko Y., Matsuda S., RA Saitoh Y., Miyamoto T., Sekine M., Homma H.; RT "Characterization of the enzymatic and structural properties of human D- RT aspartate oxidase and comparison with those of the rat and mouse enzymes."; RL Biol. Pharm. Bull. 38:298-305(2015). RN [13] RP TISSUE SPECIFICITY. RX PubMed=25689573; DOI=10.1038/tp.2015.2; RA Errico F., D'Argenio V., Sforazzini F., Iasevoli F., Squillace M., RA Guerri G., Napolitano F., Angrisano T., Di Maio A., Keller S., Vitucci D., RA Galbusera A., Chiariotti L., Bertolino A., de Bartolomeis A., Salvatore F., RA Gozzi A., Usiello A.; RT "A role for D-aspartate oxidase in schizophrenia and in schizophrenia- RT related symptoms induced by phencyclidine in mice."; RL Transl. Psychiatry 5:e512-e512(2015). RN [14] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND TISSUE SPECIFICITY. RX PubMed=28560262; DOI=10.1038/s41537-017-0015-7; RA Nuzzo T., Sacchi S., Errico F., Keller S., Palumbo O., Florio E., Punzo D., RA Napolitano F., Copetti M., Carella M., Chiariotti L., Bertolino A., RA Pollegioni L., Usiello A.; RT "Decreased free d-aspartate levels are linked to enhanced d-aspartate RT oxidase activity in the dorsolateral prefrontal cortex of schizophrenia RT patients."; RL Schizophrenia 3:16-16(2017). RN [15] RP FUNCTION, CATALYTIC ACTIVITY, AND ACTIVITY REGULATION. RX PubMed=28393897; DOI=10.1038/srep46288; RA Sacchi S., Novellis V., Paolone G., Nuzzo T., Iannotta M., Belardo C., RA Squillace M., Bolognesi P., Rosini E., Motta Z., Frassineti M., RA Bertolino A., Pollegioni L., Morari M., Maione S., Errico F., Usiello A.; RT "Olanzapine, but not clozapine, increases glutamate release in the RT prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase RT activity."; RL Sci. Rep. 7:46288-46288(2017). RN [16] RP FUNCTION, CATALYTIC ACTIVITY, AND SUBUNIT. RX PubMed=29292239; DOI=10.1016/j.bbapap.2017.12.009; RA Katane M., Kuwabara H., Nakayama K., Saitoh Y., Miyamoto T., Sekine M., RA Homma H.; RT "Rat d-aspartate oxidase is more similar to the human enzyme than the mouse RT enzyme."; RL Biochim. Biophys. Acta 1866:806-812(2018). RN [17] RP TISSUE SPECIFICITY. RX PubMed=30822420; DOI=10.1016/j.expneurol.2019.02.014; RA Nuzzo T., Feligioni M., Cristino L., Pagano I., Marcelli S., Iannuzzi F., RA Imperatore R., D'Angelo L., Petrella C., Carella M., Pollegioni L., RA Sacchi S., Punzo D., De Girolamo P., Errico F., Canu N., Usiello A.; RT "Free d-aspartate triggers NMDA receptor-dependent cell death in primary RT cortical neurons and perturbs JNK activation, Tau phosphorylation, and RT protein SUMOylation in the cerebral cortex of mice lacking d-aspartate RT oxidase activity."; RL Exp. Neurol. 317:51-65(2019). RN [18] RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=32553892; DOI=10.1016/j.bbapap.2020.140472; RA Puggioni V., Savinelli A., Miceli M., Molla G., Pollegioni L., Sacchi S.; RT "Biochemical characterization of mouse d-aspartate oxidase."; RL Biochim. Biophys. Acta 1868:140472-140472(2020). RN [19] RP CATALYTIC ACTIVITY (ISOFORMS 1 AND 3), BIOPHYSICOCHEMICAL PROPERTIES RP (ISOFORMS 1 AND 3), IDENTIFICATION BY MASS SPECTROMETRY, AND SUBCELLULAR RP LOCATION (ISOFORMS 1 AND 3). RX PubMed=33650155; DOI=10.1111/febs.15797; RA Rabattoni V., Pollegioni L., Tedeschi G., Maffioli E., Sacchi S.; RT "Cellular studies of the two main isoforms of human d-aspartate oxidase."; RL FEBS J. 288:4939-4954(2021). RN [20] RP COFACTOR, INTERACTION WITH DAOA, SUBCELLULAR LOCATION, AND S-NITROSYLATION. RX PubMed=37805834; DOI=10.1002/pro.4802; RA Rabattoni V., Motta Z., Miceli M., Molla G., Fissore A., Adinolfi S., RA Pollegioni L., Sacchi S.; RT "On the regulation of human D-aspartate oxidase."; RL Protein Sci. 32:e4802-e4802(2023). RN [21] {ECO:0007744|PDB:6RKF} RP X-RAY CRYSTALLOGRAPHY (3.22 ANGSTROMS) OF MUTANT CYS-141 AND CYS-143 IN RP COMPLEX WITH FAD, FUNCTION, CATALYTIC ACTIVITY, COFACTOR, RP BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, FAD BINDING, AND MUTAGENESIS OF RP 141-CYS--CYS-143. RX PubMed=31914658; DOI=10.1096/fj.201901703r; RA Molla G., Chaves-Sanjuan A., Savinelli A., Nardini M., Pollegioni L.; RT "Structure and kinetic properties of human d-aspartate oxidase, the enzyme- RT controlling d-aspartate levels in brain."; RL FASEB J. 34:1182-1197(2020). RN [22] RP VARIANT [LARGE SCALE ANALYSIS] LEU-136. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). RN [23] RP CHARACTERIZATION OF VARIANTS GLN-216 AND ASN-308, FUNCTION, CATALYTIC RP ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND SUBUNIT. RX PubMed=28629864; DOI=10.1016/j.bbapap.2017.06.010; RA Katane M., Kanazawa R., Kobayashi R., Oishi M., Nakayama K., Saitoh Y., RA Miyamoto T., Sekine M., Homma H.; RT "Structure-function relationships in human d-aspartate oxidase: RT characterisation of variants corresponding to known single nucleotide RT polymorphisms."; RL Biochim. Biophys. Acta 1865:1129-1140(2017). CC -!- FUNCTION: Selectively catalyzes the oxidative deamination of acidic CC amino acids (PubMed:1991137, PubMed:20603179, PubMed:23391306, CC PubMed:25747990, PubMed:28393897, PubMed:28560262, PubMed:28629864, CC PubMed:29292239, PubMed:31914658, PubMed:32553892, PubMed:9163533). CC Suppresses the level of D-aspartate in the brain, an amino acid that CC can act as an agonist for glutamate receptors (PubMed:28560262). CC Protects the organism from the toxicity of D-amino acids (By CC similarity). May also function in the intestine (By similarity). CC {ECO:0000250|UniProtKB:D3ZDM7, ECO:0000250|UniProtKB:Q922Z0, CC ECO:0000269|PubMed:1991137, ECO:0000269|PubMed:20603179, CC ECO:0000269|PubMed:23391306, ECO:0000269|PubMed:25747990, CC ECO:0000269|PubMed:28393897, ECO:0000269|PubMed:28560262, CC ECO:0000269|PubMed:28629864, ECO:0000269|PubMed:29292239, CC ECO:0000269|PubMed:31914658, ECO:0000269|PubMed:32553892, CC ECO:0000269|PubMed:9163533}. CC -!- CATALYTIC ACTIVITY: CC Reaction=D-aspartate + O2 + H2O = oxaloacetate + H2O2 + NH4(+); CC Xref=Rhea:RHEA:12512, ChEBI:CHEBI:15377, ChEBI:CHEBI:15379, CC ChEBI:CHEBI:16240, ChEBI:CHEBI:16452, ChEBI:CHEBI:28938, CC ChEBI:CHEBI:29990; EC=1.4.3.1; Evidence={ECO:0000269|PubMed:20603179, CC ECO:0000269|PubMed:23391306, ECO:0000269|PubMed:25747990, CC ECO:0000269|PubMed:28393897, ECO:0000269|PubMed:28560262, CC ECO:0000269|PubMed:28629864, ECO:0000269|PubMed:29292239, CC ECO:0000269|PubMed:31914658, ECO:0000269|PubMed:32553892, CC ECO:0000269|PubMed:9163533}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12513; CC Evidence={ECO:0000269|PubMed:20603179, ECO:0000269|PubMed:23391306, CC ECO:0000269|PubMed:25747990, ECO:0000269|PubMed:28393897, CC ECO:0000269|PubMed:28560262, ECO:0000269|PubMed:28629864, CC ECO:0000269|PubMed:29292239, ECO:0000269|PubMed:31914658, CC ECO:0000269|PubMed:32553892, ECO:0000269|PubMed:9163533}; CC -!- CATALYTIC ACTIVITY: CC Reaction=D-glutamate + O2 + H2O = 2-oxoglutarate + H2O2 + NH4(+); CC Xref=Rhea:RHEA:10028, ChEBI:CHEBI:15377, ChEBI:CHEBI:15379, CC ChEBI:CHEBI:16240, ChEBI:CHEBI:16810, ChEBI:CHEBI:28938, CC ChEBI:CHEBI:29986; Evidence={ECO:0000269|PubMed:25747990, CC ECO:0000269|PubMed:28629864, ECO:0000269|PubMed:29292239, CC ECO:0000269|PubMed:32553892}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:10029; CC Evidence={ECO:0000269|PubMed:25747990, ECO:0000269|PubMed:28629864, CC ECO:0000269|PubMed:29292239, ECO:0000269|PubMed:32553892}; CC -!- CATALYTIC ACTIVITY: [Isoform DDO-1]: CC Reaction=D-aspartate + O2 + H2O = oxaloacetate + H2O2 + NH4(+); CC Xref=Rhea:RHEA:12512, ChEBI:CHEBI:15377, ChEBI:CHEBI:15379, CC ChEBI:CHEBI:16240, ChEBI:CHEBI:16452, ChEBI:CHEBI:28938, CC ChEBI:CHEBI:29990; EC=1.4.3.1; CC Evidence={ECO:0000269|PubMed:33650155}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12513; CC Evidence={ECO:0000269|PubMed:33650155}; CC -!- CATALYTIC ACTIVITY: [Isoform 3]: CC Reaction=D-aspartate + O2 + H2O = oxaloacetate + H2O2 + NH4(+); CC Xref=Rhea:RHEA:12512, ChEBI:CHEBI:15377, ChEBI:CHEBI:15379, CC ChEBI:CHEBI:16240, ChEBI:CHEBI:16452, ChEBI:CHEBI:28938, CC ChEBI:CHEBI:29990; EC=1.4.3.1; CC Evidence={ECO:0000269|PubMed:33650155}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12513; CC Evidence={ECO:0000269|PubMed:33650155}; CC -!- COFACTOR: CC Name=FAD; Xref=ChEBI:CHEBI:57692; CC Evidence={ECO:0000269|PubMed:20603179, ECO:0000269|PubMed:31914658, CC ECO:0000269|PubMed:37805834}; CC -!- ACTIVITY REGULATION: Inhibited by the benzodiazepine olanzapine CC (PubMed:28393897). Inhibited by aminooxyacetic acid, thiolactomycin, CC malonate and meso-tartrate (PubMed:20603179, PubMed:23391306, CC PubMed:25747990). Clozapine, haloperidol and chlorpromazine have no CC effect on activity (PubMed:28393897, PubMed:28560262). Not inhibited by CC sodium, potassium, magnesium, iron, calcium, cobalt, copper, nickel, CC manganese or zinc ions (PubMed:25747990). Not inhibited by AMP, ADP, CC ATP, or cAMP (PubMed:25747990). Not inhibited by pyridoxal 5'-phosphate CC (PubMed:25747990). {ECO:0000269|PubMed:20603179, CC ECO:0000269|PubMed:23391306, ECO:0000269|PubMed:25747990, CC ECO:0000269|PubMed:28393897, ECO:0000269|PubMed:28560262}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=2.7 mM for D-aspartate (at pH 8.3) {ECO:0000269|PubMed:9163533}; CC KM=1.05 mM for D-aspartate (at 25 degrees Celsius and at pH 8.3) CC {ECO:0000269|PubMed:31914658, ECO:0000269|PubMed:32553892}; CC KM=7.2 mM for D-aspartate (at 25 degrees Celsius) CC {ECO:0000269|PubMed:31914658}; CC KM=2.1 mM for D-aspartate (at 37 degrees Celsius and at pH 8.3) CC {ECO:0000269|PubMed:25747990}; CC KM=1.77 mM for D-aspartate (at 37 degrees Celsius and at pH 8.3) CC {ECO:0000269|PubMed:28629864}; CC KM=6.8 mM for N-methyl D-aspartate (at pH 8.3) CC {ECO:0000269|PubMed:9163533}; CC KM=2.76 mM for N-methyl D-aspartate (at 25 degrees Celsius and at pH CC 8.3) {ECO:0000269|PubMed:31914658, ECO:0000269|PubMed:32553892}; CC KM=31.5 mM for D-glutamate (at 25 degrees Celsius and at pH 8.3) CC {ECO:0000269|PubMed:31914658, ECO:0000269|PubMed:32553892}; CC KM=67 mM for D-asparagine (at 25 degrees Celsius and at pH 8.3) CC {ECO:0000269|PubMed:31914658, ECO:0000269|PubMed:32553892}; CC KM=96 mM for D-histidine (at 25 degrees Celsius and at pH 8.3) CC {ECO:0000269|PubMed:31914658}; CC KM=96.2 mM for D-histidine (at 25 degrees Celsius and at pH 8.3) CC {ECO:0000269|PubMed:32553892}; CC KM=339 mM for D-proline (at 25 degrees Celsius and at pH 8.3) CC {ECO:0000269|PubMed:31914658}; CC KM=339.2 mM for D-proline (at 25 degrees Celsius and at pH 8.3) CC {ECO:0000269|PubMed:32553892}; CC Note=kcat is 81.3 sec(-1) with D-aspartate as substrate (at 25 CC degrees Celsius and at pH 8.3) (PubMed:32553892, PubMed:31914658). CC kcat is 229 sec(-1) with D-aspartate as substrate (at 25 degrees CC Celsius) (PubMed:31914658). kcat is 68.4 sec(-1) with D-aspartate as CC substrate (at 37 degrees Celsius and at pH 8.3) (PubMed:25747990). CC kcat is 45.8 sec(-1) with D-aspartate as substrate (at 37 degrees CC Celsius and at pH 8.3) (PubMed:28629864). kcat is 73.6 sec(-1) with CC N-methyl D-aspartate as substrate (at 25 degrees Celsius and at pH CC 8.3) (PubMed:32553892, PubMed:31914658). kcat is 11.3 sec(-1) with D- CC glutamate as substrate (at 25 degrees Celsius and at pH 8.3) CC (PubMed:32553892, PubMed:31914658). kcat is 8.3 sec(-1) with D- CC asparagine as substrate (at 25 degrees Celsius and at pH 8.3) CC (PubMed:32553892, PubMed:31914658). kcat is 1.2 sec(-1) with D- CC histidine as substrate (at 25 degrees Celsius and at pH 8.3) CC (PubMed:32553892, PubMed:31914658). kcat is 1.2 sec(-1) with D- CC proline as substrate (at 25 degrees Celsius and at pH 8.3) CC (PubMed:32553892, PubMed:31914658). {ECO:0000269|PubMed:25747990, CC ECO:0000269|PubMed:28629864, ECO:0000269|PubMed:31914658, CC ECO:0000269|PubMed:32553892}; CC pH dependence: CC Optimum pH is 8.3-12.5. {ECO:0000269|PubMed:25747990}; CC Temperature dependence: CC Optimum temperature is 45 degrees Celsius. CC {ECO:0000269|PubMed:25747990}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: [Isoform DDO-1]: CC Kinetic parameters: CC KM=0.29 mM for D-aspartate (at 25 degrees Celsius and at pH 8) CC {ECO:0000269|PubMed:33650155}; CC Note=kcat is 27.4 sec(-1) with D-aspartate as substrate (at 25 CC degrees Celsius and at pH 8.3). {ECO:0000269|PubMed:33650155}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: [Isoform 3]: CC Kinetic parameters: CC KM=0.44 mM for D-aspartate (at 25 degrees Celsius and at pH 8) CC {ECO:0000269|PubMed:33650155}; CC Note=kcat is 27.8 sec(-1) with D-aspartate as substrate (at 25 CC degrees Celsius and at pH 8.3). {ECO:0000269|PubMed:33650155}; CC -!- SUBUNIT: Monomer (PubMed:28629864, PubMed:29292239, PubMed:31914658). CC Interacts with PEX5; the interaction is direct and required for CC localization of DDO to the peroxisome (PubMed:9820813). Interacts with CC DAOA; the interaction is direct and increases the degradation rate of CC DDO (PubMed:37805834). {ECO:0000269|PubMed:28629864, CC ECO:0000269|PubMed:29292239, ECO:0000269|PubMed:31914658, CC ECO:0000269|PubMed:37805834, ECO:0000269|PubMed:9820813}. CC -!- SUBCELLULAR LOCATION: Peroxisome matrix {ECO:0000269|PubMed:1991137, CC ECO:0000269|PubMed:37805834}. Cytoplasm, cytosol CC {ECO:0000269|PubMed:37805834}. Note=Active in the peroxisomal matrix. CC {ECO:0000269|PubMed:37805834}. CC -!- SUBCELLULAR LOCATION: [Isoform DDO-1]: Peroxisome matrix CC {ECO:0000269|PubMed:33650155}. CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Peroxisome matrix CC {ECO:0000269|PubMed:33650155}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=DDO-1; Synonyms=A, DASPO_341 {ECO:0000303|PubMed:33650155}; CC IsoId=Q99489-1; Sequence=Displayed; CC Name=DDO-2; Synonyms=DASPO_282 {ECO:0000303|PubMed:33650155}; CC IsoId=Q99489-2; Sequence=VSP_001269; CC Name=3; Synonyms=DASPO_369 {ECO:0000303|PubMed:33650155}; CC IsoId=Q99489-3; Sequence=VSP_037664; CC Name=4; CC IsoId=Q99489-4; Sequence=VSP_037664, VSP_001269; CC -!- TISSUE SPECIFICITY: Expressed in epithelial cells of the proximal CC nephron tubules in the renal cortex (at protein level) CC (PubMed:12209855, PubMed:1991137). In the brain, expressed in the CC frontal, temporal, and occipital lobes of the cortex, hippocampus, CC striatum, diencephalon, brainstem, cerebellum, spinal cord, plexus CC choroiderus and ependyma (at protein level) (PubMed:12209855, CC PubMed:28560262). Expression is increased in the prefrontal cortex of CC schizophrenic patients (PubMed:25689573). Levels are normal in the CC superior frontal gyrus of patients with Alzheimer's disease CC (PubMed:30822420). {ECO:0000269|PubMed:12209855, CC ECO:0000269|PubMed:1991137, ECO:0000269|PubMed:25689573, CC ECO:0000269|PubMed:28560262, ECO:0000269|PubMed:30822420}. CC -!- PTM: May be S-nitrosylated. {ECO:0000269|PubMed:37805834}. CC -!- MISCELLANEOUS: [Isoform 3]: Found in the hippocampus of female patients CC affected by Alzheimer's disease (PubMed:33650155). CC {ECO:0000269|PubMed:33650155}. CC -!- SIMILARITY: Belongs to the DAMOX/DASOX family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; D89858; BAA14031.1; -; mRNA. DR EMBL; AK293029; BAF85718.1; -; mRNA. DR EMBL; AL050350; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471051; EAW48316.1; -; Genomic_DNA. DR EMBL; CH471051; EAW48317.1; -; Genomic_DNA. DR EMBL; BC032786; AAH32786.3; -; mRNA. DR EMBL; DN990727; -; NOT_ANNOTATED_CDS; mRNA. DR CCDS; CCDS5082.2; -. [Q99489-1] DR CCDS; CCDS5083.2; -. [Q99489-2] DR PIR; JC5438; JC5438. DR PIR; JC5439; JC5439. DR RefSeq; NP_001359037.1; NM_001372108.2. [Q99489-1] DR PDB; 6RKF; X-ray; 3.22 A; A/B/C/D/E/F=1-341. DR PDBsum; 6RKF; -. DR AlphaFoldDB; Q99489; -. DR SMR; Q99489; -. DR BioGRID; 114098; 3. DR FunCoup; Q99489; 349. DR IntAct; Q99489; 2. DR STRING; 9606.ENSP00000357920; -. DR BindingDB; Q99489; -. DR ChEMBL; CHEMBL5887; -. DR iPTMnet; Q99489; -. DR PhosphoSitePlus; Q99489; -. DR BioMuta; DDO; -. DR DMDM; 2494037; -. DR jPOST; Q99489; -. DR MassIVE; Q99489; -. DR PaxDb; 9606-ENSP00000357920; -. DR PeptideAtlas; Q99489; -. DR ProteomicsDB; 78291; -. [Q99489-1] DR ProteomicsDB; 78292; -. [Q99489-2] DR ProteomicsDB; 78293; -. [Q99489-3] DR ProteomicsDB; 78294; -. [Q99489-4] DR Antibodypedia; 32325; 223 antibodies from 24 providers. DR DNASU; 8528; -. DR Ensembl; ENST00000368923.8; ENSP00000357919.4; ENSG00000203797.13. [Q99489-2] DR Ensembl; ENST00000368924.9; ENSP00000357920.4; ENSG00000203797.13. [Q99489-1] DR GeneID; 8528; -. DR KEGG; hsa:8528; -. DR MANE-Select; ENST00000368924.9; ENSP00000357920.4; NM_001372108.2; NP_001359037.1. DR UCSC; uc003puc.4; human. [Q99489-1] DR AGR; HGNC:2727; -. DR ClinPGx; PA27194; -. DR CTD; 8528; -. DR DisGeNET; 8528; -. DR GeneCards; DDO; -. DR HGNC; HGNC:2727; DDO. DR HPA; ENSG00000203797; Tissue enhanced (heart). DR MIM; 124450; gene. DR OpenTargets; ENSG00000203797; -. DR VEuPathDB; HostDB:ENSG00000203797; -. DR eggNOG; KOG3923; Eukaryota. DR GeneTree; ENSGT00390000018635; -. DR HOGENOM; CLU_034311_0_2_1; -. DR InParanoid; Q99489; -. DR OMA; DLWELQP; -. DR OrthoDB; 2015447at2759; -. DR PAN-GO; Q99489; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q99489; -. DR BRENDA; 1.4.3.1; 2681. DR PathwayCommons; Q99489; -. DR Reactome; R-HSA-389661; Glyoxylate metabolism and glycine degradation. DR Reactome; R-HSA-9033241; Peroxisomal protein import. DR SABIO-RK; Q99489; -. DR SignaLink; Q99489; -. DR Agora; ENSG00000203797; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 8528; 8 hits in 1143 CRISPR screens. DR ChiTaRS; DDO; human. DR GeneWiki; DDO_(gene); -. DR GenomeRNAi; 8528; -. DR Pharos; Q99489; Tchem. DR PRO; PR:Q99489; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; Q99489; protein. DR Bgee; ENSG00000203797; Expressed in heart left ventricle and 136 other cell types or tissues. DR ExpressionAtlas; Q99489; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005782; C:peroxisomal matrix; ISS:UniProtKB. DR GO; GO:0005777; C:peroxisome; IDA:UniProtKB. DR GO; GO:0008445; F:D-aspartate oxidase activity; IDA:UniProtKB. DR GO; GO:0047821; F:D-glutamate oxidase activity; IEA:RHEA. DR GO; GO:0071949; F:FAD binding; IDA:UniProtKB. DR GO; GO:0006531; P:aspartate metabolic process; IEA:Ensembl. DR GO; GO:0019478; P:D-amino acid catabolic process; IDA:UniProtKB. DR GO; GO:0007625; P:grooming behavior; IEA:Ensembl. DR GO; GO:0042445; P:hormone metabolic process; IEA:Ensembl. DR GO; GO:0007320; P:insemination; IEA:Ensembl. DR GO; GO:0170035; P:L-amino acid catabolic process; IEA:UniProtKB-ARBA. DR GO; GO:0006533; P:L-aspartate catabolic process; IDA:UniProtKB. DR GO; GO:0050877; P:nervous system process; IMP:UniProtKB. DR GO; GO:0170040; P:proteinogenic amino acid catabolic process; IEA:UniProtKB-ARBA. DR GO; GO:0010646; P:regulation of cell communication; IEA:Ensembl. DR FunFam; 3.30.9.10:FF:000004; D-amino-acid oxidase; 1. DR FunFam; 3.40.50.720:FF:000551; D-aspartate oxidase; 1. DR Gene3D; 3.30.9.10; D-Amino Acid Oxidase, subunit A, domain 2; 1. DR Gene3D; 3.40.50.720; NAD(P)-binding Rossmann-like Domain; 1. DR InterPro; IPR006181; D-amino_acid_oxidase_CS. DR InterPro; IPR023209; DAO. DR InterPro; IPR006076; FAD-dep_OxRdtase. DR PANTHER; PTHR11530; D-AMINO ACID OXIDASE; 1. DR PANTHER; PTHR11530:SF11; D-ASPARTATE OXIDASE; 1. DR Pfam; PF01266; DAO; 1. DR PIRSF; PIRSF000189; D-aa_oxidase; 1. DR SUPFAM; SSF54373; FAD-linked reductases, C-terminal domain; 1. DR SUPFAM; SSF51971; Nucleotide-binding domain; 1. DR PROSITE; PS00677; DAO; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasm; FAD; Flavoprotein; KW Oxidoreductase; Peroxisome; Proteomics identification; Reference proteome. FT CHAIN 1..341 FT /note="D-aspartate oxidase" FT /id="PRO_0000162770" FT MOTIF 339..341 FT /note="Microbody targeting signal" FT /evidence="ECO:0000305|PubMed:9820813" FT BINDING 36 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:31914658, FT ECO:0007744|PDB:6RKF" FT BINDING 37 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:31914658, FT ECO:0007744|PDB:6RKF" FT BINDING 43 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:31914658, FT ECO:0007744|PDB:6RKF" FT BINDING 44 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:31914658, FT ECO:0007744|PDB:6RKF" FT BINDING 50 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:31914658, FT ECO:0007744|PDB:6RKF" FT BINDING 307 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:31914658, FT ECO:0007744|PDB:6RKF" FT BINDING 311 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:31914658, FT ECO:0007744|PDB:6RKF" FT BINDING 312 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:31914658, FT ECO:0007744|PDB:6RKF" FT VAR_SEQ 1 FT /note="M -> MRPARHWETRFGARDFGGFQDCFFRDRLM (in isoform 3 and FT isoform 4)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334, ECO:0000303|Ref.6" FT /id="VSP_037664" FT VAR_SEQ 95..153 FT /note="Missing (in isoform DDO-2 and isoform 4)" FT /evidence="ECO:0000303|PubMed:9163533, ECO:0000303|Ref.6" FT /id="VSP_001269" FT VARIANT 136 FT /note="F -> L (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036244" FT VARIANT 189 FT /note="Q -> E (in dbSNP:rs17622)" FT /id="VAR_014939" FT VARIANT 216 FT /note="R -> Q (decreases activity; decreases FAD binding; FT dbSNP:rs147072212)" FT /evidence="ECO:0000269|PubMed:28629864" FT /id="VAR_088719" FT VARIANT 230 FT /note="H -> Y (in dbSNP:rs17621)" FT /id="VAR_014940" FT VARIANT 255 FT /note="L -> R (in dbSNP:rs17623)" FT /id="VAR_014941" FT VARIANT 308 FT /note="S -> N (decreases activity; decreases FAD binding; FT dbSNP:rs140566457)" FT /evidence="ECO:0000269|PubMed:28629864" FT /id="VAR_088720" FT MUTAGEN 141..143 FT /note="CEC->YEG: Slightly decreases activity." FT /evidence="ECO:0000269|PubMed:31914658" FT CONFLICT 278 FT /note="R -> S (in Ref. 2; BAF85718)" FT /evidence="ECO:0000305" FT STRAND 6..9 FT /evidence="ECO:0007829|PDB:6RKF" FT HELIX 13..23 FT /evidence="ECO:0007829|PDB:6RKF" FT STRAND 26..28 FT /evidence="ECO:0007829|PDB:6RKF" FT TURN 43..45 FT /evidence="ECO:0007829|PDB:6RKF" FT HELIX 61..79 FT /evidence="ECO:0007829|PDB:6RKF" FT HELIX 84..87 FT /evidence="ECO:0007829|PDB:6RKF" FT STRAND 89..100 FT /evidence="ECO:0007829|PDB:6RKF" FT TURN 108..112 FT /evidence="ECO:0007829|PDB:6RKF" FT STRAND 113..118 FT /evidence="ECO:0007829|PDB:6RKF" FT HELIX 121..124 FT /evidence="ECO:0007829|PDB:6RKF" FT STRAND 131..141 FT /evidence="ECO:0007829|PDB:6RKF" FT HELIX 143..157 FT /evidence="ECO:0007829|PDB:6RKF" FT STRAND 161..163 FT /evidence="ECO:0007829|PDB:6RKF" FT HELIX 169..172 FT /evidence="ECO:0007829|PDB:6RKF" FT TURN 173..175 FT /evidence="ECO:0007829|PDB:6RKF" FT STRAND 177..181 FT /evidence="ECO:0007829|PDB:6RKF" FT HELIX 184..186 FT /evidence="ECO:0007829|PDB:6RKF" FT HELIX 187..190 FT /evidence="ECO:0007829|PDB:6RKF" FT STRAND 197..207 FT /evidence="ECO:0007829|PDB:6RKF" FT STRAND 213..216 FT /evidence="ECO:0007829|PDB:6RKF" FT STRAND 223..225 FT /evidence="ECO:0007829|PDB:6RKF" FT STRAND 228..234 FT /evidence="ECO:0007829|PDB:6RKF" FT STRAND 238..240 FT /evidence="ECO:0007829|PDB:6RKF" FT HELIX 248..261 FT /evidence="ECO:0007829|PDB:6RKF" FT HELIX 263..266 FT /evidence="ECO:0007829|PDB:6RKF" FT STRAND 269..280 FT /evidence="ECO:0007829|PDB:6RKF" FT STRAND 285..290 FT /evidence="ECO:0007829|PDB:6RKF" FT STRAND 293..295 FT /evidence="ECO:0007829|PDB:6RKF" FT STRAND 299..304 FT /evidence="ECO:0007829|PDB:6RKF" FT HELIX 307..309 FT /evidence="ECO:0007829|PDB:6RKF" FT HELIX 314..333 FT /evidence="ECO:0007829|PDB:6RKF" FT CONFLICT Q99489-4:9 FT /note="T -> N (in Ref. 6; DN990727)" FT /evidence="ECO:0000305" SQ SEQUENCE 341 AA; 37535 MW; 8CAE7501FB7F215C CRC64; MDTARIAVVG AGVVGLSTAV CISKLVPRCS VTIISDKFTP DTTSDVAAGM LIPHTYPDTP IHTQKQWFRE TFNHLFAIAN SAEAGDAGVH LVSGWQIFQS TPTEEVPFWA DVVLGFRKMT EAELKKFPQY VFGQAFTTLK CECPAYLPWL EKRIKGSGGW TLTRRIEDLW ELHPSFDIVV NCSGLGSRQL AGDSKIFPVR GQVLQVQAPW VEHFIRDGSG LTYIYPGTSH VTLGGTRQKG DWNLSPDAEN SREILSRCCA LEPSLHGACN IREKVGLRPY RPGVRLQTEL LARDGQRLPV VHHYGHGSGG ISVHWGTALE AARLVSECVH ALRTPIPKSN L // ID REST_HUMAN Reviewed; 1097 AA. AC Q13127; A2RUE0; B9EGJ0; Q12956; Q12957; Q13134; Q59ER1; Q8IWI3; DT 12-DEC-2006, integrated into UniProtKB/Swiss-Prot. DT 18-MAY-2010, sequence version 3. DT 28-JAN-2026, entry version 209. DE RecName: Full=RE1-silencing transcription factor; DE AltName: Full=Neural-restrictive silencer factor; DE AltName: Full=X2 box repressor; GN Name=REST; Synonyms=NRSF, XBR; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION. RX PubMed=7697725; DOI=10.1016/0092-8674(95)90298-8; RA Chong J.A., Tapia-Ramirez J., Kim S., Toledo-Aral J.J., Zheng Y., RA Boutros M.C., Altshuller Y.M., Frohman M.A., Kraner S.D., Mandel G.; RT "REST: a mammalian silencer protein that restricts sodium channel gene RT expression to neurons."; RL Cell 80:949-957(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), NUCLEOTIDE SEQUENCE [MRNA] OF 1-599 RP (ISOFORM 1), AND FUNCTION. RX PubMed=7871435; DOI=10.1126/science.7871435; RA Schoenherr C.J., Anderson D.J.; RT "The neuron-restrictive silencer factor (NRSF): a coordinate repressor of RT multiple neuron-specific genes."; RL Science 267:1360-1363(1995). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY, AND RP VARIANT LEU-797. RX PubMed=8568247; RA Scholl T., Stevens M.B., Mahanta S., Strominger J.L.; RT "A zinc finger protein that represses transcription of the human MHC class RT II gene, DPA."; RL J. Immunol. 156:1448-1457(1996). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., RA Ohara O., Nagase T., Kikuno R.F.; RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ILE-626. RC TISSUE=Testis, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP ALTERNATIVE SPLICING (ISOFORMS 3 AND 4). RX PubMed=10521596; DOI=10.1016/s0169-328x(99)00196-5; RA Palm K., Metsis M., Timmusk T.; RT "Neuron-specific splicing of zinc finger transcription factor REST/NRSF/XBR RT is frequent in neuroblastomas and conserved in human, mouse and rat."; RL Brain Res. Mol. Brain Res. 72:30-39(1999). RN [9] RP FUNCTION, AND INTERACTION WITH RCOR1. RX PubMed=10449787; DOI=10.1073/pnas.96.17.9873; RA Andres M.E., Burger C., Peral-Rubio M.J., Battaglioli E., Anderson M.E., RA Grimes J., Dallman J., Ballas N., Mandel G.; RT "CoREST: a functional corepressor required for regulation of neural- RT specific gene expression."; RL Proc. Natl. Acad. Sci. U.S.A. 96:9873-9878(1999). RN [10] RP FUNCTION, AND INTERACTION WITH RCOR1 AND SIN3A. RX PubMed=10734093; DOI=10.1074/jbc.275.13.9461; RA Grimes J.A., Nielsen S.J., Battaglioli E., Miska E.A., Speh J.C., RA Berry D.L., Atouf F., Holdener B.C., Mandel G., Kouzarides T.; RT "The co-repressor mSin3A is a functional component of the REST-CoREST RT repressor complex."; RL J. Biol. Chem. 275:9461-9467(2000). RN [11] RP FUNCTION. RX PubMed=11779185; DOI=10.1006/bbrc.2001.6194; RA Tabuchi A., Yamada T., Sasagawa S., Naruse Y., Mori N., Tsuda M.; RT "REST4-mediated modulation of REST/NRSF-silencing function during BDNF gene RT promoter activation."; RL Biochem. Biophys. Res. Commun. 290:415-420(2002). RN [12] RP FUNCTION, AND SUBCELLULAR LOCATION (ISOFORM 3). RX PubMed=11741002; DOI=10.1016/s0197-0186(01)00091-2; RA Magin A., Lietz M., Cibelli G., Thiel G.; RT "RE-1 silencing transcription factor-4 (REST4) is neither a transcriptional RT repressor nor a de-repressor."; RL Neurochem. Int. 40:195-202(2002). RN [13] RP FUNCTION. RX PubMed=12399542; DOI=10.1126/science.1076469; RA Lunyak V.V., Burgess R., Prefontaine G.G., Nelson C., Sze S.-H., RA Chenoweth J., Schwartz P., Pevzner P.A., Glass C., Mandel G., RA Rosenfeld M.G.; RT "Corepressor-dependent silencing of chromosomal regions encoding neuronal RT genes."; RL Science 298:1747-1752(2002). RN [14] RP ERRATUM OF PUBMED:12399542. RA Lunyak V.V., Burgess R., Prefontaine G.G., Nelson C., Sze S.-H., RA Chenoweth J., Schwartz P., Pevzner P.A., Glass C., Mandel G., RA Rosenfeld M.G.; RL Science 299:1663-1663(2003). RN [15] RP INTERACTION WITH PRICKLE1. RC TISSUE=Brain; RX PubMed=14645515; DOI=10.1128/mcb.23.24.9025-9031.2003; RA Shimojo M., Hersh L.B.; RT "REST/NRSF-interacting LIM domain protein, a putative nuclear translocation RT receptor."; RL Mol. Cell. Biol. 23:9025-9031(2003). RN [16] RP INTERACTION WITH PRICKLE1, SUBCELLULAR LOCATION (ISOFORMS 1; 2; 3 AND 4), RP AND MUTAGENESIS OF 512-LYS--LYS-522. RX PubMed=16442230; DOI=10.1016/j.neulet.2005.12.080; RA Shimojo M.; RT "Characterization of the nuclear targeting signal of REST/NRSF."; RL Neurosci. Lett. 398:161-166(2006). RN [17] RP FUNCTION, INTERACTION WITH CDYL; EHMT1 AND EHMT2, AND IDENTIFICATION IN A RP COMPLEX WITH CDYL; SETB1; EHMT1; EHMT2 AND WIZ. RX PubMed=19061646; DOI=10.1016/j.molcel.2008.10.025; RA Mulligan P., Westbrook T.F., Ottinger M., Pavlova N., Chang B., Macia E., RA Shi Y.J., Barretina J., Liu J., Howley P.M., Elledge S.J., Shi Y.; RT "CDYL bridges REST and histone methyltransferases for gene repression and RT suppression of cellular transformation."; RL Mol. Cell 32:718-726(2008). RN [18] RP INTERACTION WITH FBXW11 AND BTRC, DEVELOPMENTAL STAGE, PHOSPHORYLATION, RP UBIQUITINATION BY BTRC, AND MUTAGENESIS OF 1009-GLU--SER-1013. RX PubMed=18354482; DOI=10.1038/nature06641; RA Guardavaccaro D., Frescas D., Dorrello N.V., Peschiaroli A., Multani A.S., RA Cardozo T., Lasorella A., Iavarone A., Chang S., Hernando E., Pagano M.; RT "Control of chromosome stability by the beta-TrCP-REST-Mad2 axis."; RL Nature 452:365-369(2008). RN [19] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [20] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-864, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [21] RP INTERACTION WITH ZFP90. RX PubMed=21284946; DOI=10.1016/j.yjmcc.2011.01.017; RA Hata L., Murakami M., Kuwahara K., Nakagawa Y., Kinoshita H., Usami S., RA Yasuno S., Fujiwara M., Kuwabara Y., Minami T., Yamada Y., Yamada C., RA Nakao K., Ueshima K., Nishikimi T., Nakao K.; RT "Zinc-finger protein 90 negatively regulates neuron-restrictive silencer RT factor-mediated transcriptional repression of fetal cardiac genes."; RL J. Mol. Cell. Cardiol. 50:972-981(2011). RN [22] RP FUNCTION, INTERACTION WITH USP7, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, RP INDUCTION, UBIQUITINATION BY BTRC, DEUBIQUITINATION BY USP7, AND RP MUTAGENESIS OF SER-313 AND SER-1042. RX PubMed=21258371; DOI=10.1038/ncb2153; RA Huang Z., Wu Q., Guryanova O.A., Cheng L., Shou W., Rich J.N., Bao S.; RT "Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural RT progenitor cells."; RL Nat. Cell Biol. 13:142-152(2011). RN [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-864, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [24] RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, RP AND INDUCTION BY WNT SIGNALING; AGING AND OXIDATIVE STRESS. RX PubMed=24670762; DOI=10.1038/nature13163; RA Lu T., Aron L., Zullo J., Pan Y., Kim H., Chen Y., Yang T.H., Kim H.M., RA Drake D., Liu X.S., Bennett D.A., Colaiacovo M.P., Yankner B.A.; RT "REST and stress resistance in ageing and Alzheimer's disease."; RL Nature 507:448-454(2014). RN [25] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=26053433; DOI=10.1038/srep11207; RA Lee N.S., Evgrafov O.V., Souaiaia T., Bonyad A., Herstein J., Lee J.Y., RA Kim J., Ning Y., Sixto M., Weitz A.C., Lenz H.J., Wang K., Knowles J.A., RA Press M.F., Salvaterra P.M., Shung K.K., Chow R.H.; RT "Non-coding RNAs derived from an alternatively spliced REST transcript RT (REST-003) regulate breast cancer invasiveness."; RL Sci. Rep. 5:11207-11207(2015). RN [26] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=27531581; DOI=10.1038/srep31355; RA Cavadas M.A., Mesnieres M., Crifo B., Manresa M.C., Selfridge A.C., RA Keogh C.E., Fabian Z., Scholz C.C., Nolan K.A., Rocha L.M., Tambuwala M.M., RA Brown S., Wdowicz A., Corbett D., Murphy K.J., Godson C., Cummins E.P., RA Taylor C.T., Cheong A.; RT "REST is a hypoxia-responsive transcriptional repressor."; RL Sci. Rep. 6:31355-31355(2016). RN [27] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=30684677; DOI=10.1016/j.neulet.2019.01.042; RA Kawamura M., Sato S., Matsumoto G., Fukuda T., Shiba-Fukushima K., Noda S., RA Takanashi M., Mori N., Hattori N.; RT "Loss of nuclear REST/NRSF in aged-dopaminergic neurons in Parkinson's RT disease patients."; RL Neurosci. Lett. 699:59-63(2019). RN [28] RP STRUCTURE BY NMR OF 43-57 IN COMPLEX WITH SIN3B, AND INTERACTION WITH RP SIN3B. RX PubMed=16288918; DOI=10.1016/j.jmb.2005.10.008; RA Nomura M., Uda-Tochio H., Murai K., Mori N., Nishimura Y.; RT "The neural repressor NRSF/REST binds the PAH1 domain of the Sin3 RT corepressor by using its distinct short hydrophobic helix."; RL J. Mol. Biol. 354:903-915(2005). RN [29] RP INVOLVEMENT IN WT6, VARIANTS WT6 PRO-160; TYR-290; ARG-322 AND GLN-412, RP CHARACTERIZATION OF VARIANT PRO-160; TYR-290 AND ARG-322, FUNCTION, AND RP MUTAGENESIS OF GLU-91; MET-420; SER-593; ALA-642 AND HIS-918. RX PubMed=26551668; DOI=10.1038/ng.3440; RA Mahamdallie S.S., Hanks S., Karlin K.L., Zachariou A., Perdeaux E.R., RA Ruark E., Shaw C.A., Renwick A., Ramsay E., Yost S., Elliott A., Birch J., RA Capra M., Gray J., Hale J., Kingston J., Levitt G., McLean T., Sheridan E., RA Renwick A., Seal S., Stiller C., Sebire N., Westbrook T.F., Rahman N.; RT "Mutations in the transcriptional repressor REST predispose to Wilms RT tumor."; RL Nat. Genet. 47:1471-1474(2015). RN [30] RP INVOLVEMENT IN GINGF5, AND VARIANT GINGF5 437-LEU--GLU-1097 DEL. RX PubMed=28686854; DOI=10.1016/j.ajhg.2017.06.006; RG Baylor-Hopkins Center for Mendelian Genomics; RA Bayram Y., White J.J., Elcioglu N., Cho M.T., Zadeh N., Gedikbasi A., RA Palanduz S., Ozturk S., Cefle K., Kasapcopur O., Coban Akdemir Z., RA Pehlivan D., Begtrup A., Carvalho C.M.B., Paine I.S., Mentes A., RA Bektas-Kayhan K., Karaca E., Jhangiani S.N., Muzny D.M., Gibbs R.A., RA Lupski J.R.; RT "REST final-exon-truncating mutations cause hereditary gingival RT fibromatosis."; RL Am. J. Hum. Genet. 101:149-156(2017). RN [31] RP INVOLVEMENT IN DFNA27, AND ALTERNATIVE SPLICING (ISOFORM 3). RX PubMed=29961578; DOI=10.1016/j.cell.2018.06.004; RA Nakano Y., Kelly M.C., Rehman A.U., Boger E.T., Morell R.J., Kelley M.W., RA Friedman T.B., Banfi B.; RT "Defects in the Alternative Splicing-Dependent Regulation of REST Cause RT Deafness."; RL Cell 174:536-548.E21(2018). CC -!- FUNCTION: Transcriptional repressor which binds neuron-restrictive CC silencer element (NRSE) and represses neuronal gene transcription in CC non-neuronal cells (PubMed:11741002, PubMed:11779185, PubMed:12399542, CC PubMed:26551668, PubMed:7697725, PubMed:7871435, PubMed:8568247). CC Restricts the expression of neuronal genes by associating with two CC distinct corepressors, SIN3A and RCOR1, which in turn recruit histone CC deacetylase to the promoters of REST-regulated genes (PubMed:10449787, CC PubMed:10734093). Mediates repression by recruiting the BHC complex at CC RE1/NRSE sites which acts by deacetylating and demethylating specific CC sites on histones, thereby acting as a chromatin modifier (By CC similarity). Transcriptional repression by REST-CDYL via the CC recruitment of histone methyltransferase EHMT2 may be important in CC transformation suppression (PubMed:19061646). Represses the expression CC of SRRM4 in non-neural cells to prevent the activation of neural- CC specific splicing events and to prevent production of REST isoform 3 CC (By similarity). Repressor activity may be inhibited by forming CC heterodimers with isoform 3, thereby preventing binding to NRSE or CC binding to corepressors and leading to derepression of target genes CC (PubMed:11779185). Also maintains repression of neuronal genes in CC neural stem cells, and allows transcription and differentiation into CC neurons by dissociation from RE1/NRSE sites of target genes (By CC similarity). Thereby is involved in maintaining the quiescent state of CC adult neural stem cells and preventing premature differentiation into CC mature neurons (PubMed:21258371). Plays a role in the developmental CC switch in synaptic NMDA receptor composition during postnatal CC development, by repressing GRIN2B expression and thereby altering NMDA CC receptor properties from containing primarily GRIN2B to primarily CC GRIN2A subunits (By similarity). Acts as a regulator of osteoblast CC differentiation (By similarity). Key repressor of gene expression in CC hypoxia; represses genes in hypoxia by direct binding to an RE1/NRSE CC site on their promoter regions (PubMed:27531581). May also function in CC stress resistance in the brain during aging; possibly by regulating CC expression of genes involved in cell death and in the stress response CC (PubMed:24670762). Repressor of gene expression in the hippocampus CC after ischemia by directly binding to RE1/NRSE sites and recruiting CC SIN3A and RCOR1 to promoters of target genes, thereby promoting changes CC in chromatin modifications and ischemia-induced cell death (By CC similarity). After ischemia, might play a role in repression of miR-132 CC expression in hippocampal neurons, thereby leading to neuronal cell CC death (By similarity). Negatively regulates the expression of SRRM3 in CC breast cancer cell lines (PubMed:26053433). CC {ECO:0000250|UniProtKB:O54963, ECO:0000250|UniProtKB:Q8VIG1, CC ECO:0000269|PubMed:10449787, ECO:0000269|PubMed:10734093, CC ECO:0000269|PubMed:11741002, ECO:0000269|PubMed:11779185, CC ECO:0000269|PubMed:12399542, ECO:0000269|PubMed:19061646, CC ECO:0000269|PubMed:21258371, ECO:0000269|PubMed:24670762, CC ECO:0000269|PubMed:26053433, ECO:0000269|PubMed:26551668, CC ECO:0000269|PubMed:27531581, ECO:0000269|PubMed:7697725, CC ECO:0000269|PubMed:7871435, ECO:0000269|PubMed:8568247}. CC -!- FUNCTION: [Isoform 3]: Binds to the 3' region of the neuron-restrictive CC silencer element (NRSE), with lower affinity than full-length REST CC isoform 1 (By similarity). Exhibits weaker repressor activity compared CC to isoform 1 (PubMed:11779185). May negatively regulate the repressor CC activity of isoform 1 by binding to isoform 1, thereby preventing its CC binding to NRSE and leading to derepression of target genes CC (PubMed:11779185). However, in another study, does not appear to be CC implicated in repressor activity of a NRSE motif-containing reporter CC construct nor in inhibitory activity on the isoform 1 transcriptional CC repressor activity (PubMed:11741002). Post-transcriptional inactivation CC of REST by SRRM4-dependent alternative splicing into isoform 3 is CC required in mechanosensory hair cells in the inner ear for derepression CC of neuronal genes and hearing (By similarity). CC {ECO:0000250|UniProtKB:Q8VIG1, ECO:0000269|PubMed:11741002, CC ECO:0000269|PubMed:11779185}. CC -!- SUBUNIT: Isoform 1 and isoform 3 form heterodimers (By similarity). CC Isoform 3: Forms homodimers and homooligomers; binds to the neuron- CC restrictive silencer element (NRSE) as monomer (By similarity). CC Interacts with SIN3A, SIN3B and RCOR1 (PubMed:10449787, CC PubMed:10734093, PubMed:16288918). Interacts with CDYL CC (PubMed:19061646). Interacts with EHMT1 and EHMT2 only in the presence CC of CDYL (PubMed:19061646). Part of a complex containing at least CDYL, CC REST, WIZ, SETB1, EHMT1 and EHMT2 (PubMed:19061646). Interacts (via CC zinc-finger DNA-binding domain) with ZFP90 (via N- and C-termini); the CC interaction inhibits REST repressor activity (PubMed:21284946). CC Interacts (via C2H2-type zinc finger 5) with PRICKLE1 (PubMed:14645515, CC PubMed:16442230). Interacts with FBXW11 and BTRC (PubMed:18354482). CC Interacts with USP7 (PubMed:21258371). {ECO:0000250|UniProtKB:Q8VIG1, CC ECO:0000269|PubMed:10449787, ECO:0000269|PubMed:10734093, CC ECO:0000269|PubMed:14645515, ECO:0000269|PubMed:16288918, CC ECO:0000269|PubMed:16442230, ECO:0000269|PubMed:18354482, CC ECO:0000269|PubMed:19061646, ECO:0000269|PubMed:21258371, CC ECO:0000269|PubMed:21284946}. CC -!- INTERACTION: CC Q13127; Q9Y297: BTRC; NbExp=10; IntAct=EBI-926706, EBI-307461; CC Q13127; Q9UKB1: FBXW11; NbExp=3; IntAct=EBI-926706, EBI-355189; CC Q13127; P07900: HSP90AA1; NbExp=4; IntAct=EBI-926706, EBI-296047; CC Q13127; P41229: KDM5C; NbExp=3; IntAct=EBI-926706, EBI-1246541; CC Q13127; P51532: SMARCA4; NbExp=2; IntAct=EBI-926706, EBI-302489; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16442230, CC ECO:0000269|PubMed:21258371, ECO:0000269|PubMed:24670762, CC ECO:0000269|PubMed:27531581, ECO:0000269|PubMed:30684677}. Cytoplasm CC {ECO:0000269|PubMed:24670762, ECO:0000269|PubMed:27531581, CC ECO:0000269|PubMed:30684677}. Note=Colocalizes with ZFP90 in the CC nucleus (By similarity). In response to hypoxia, there is a more CC pronounced increase in levels in the nucleus as compared to the CC cytoplasm (PubMed:27531581). In aging neurons, increased levels in the CC nucleus as compared to the cytoplasm (PubMed:24670762, CC PubMed:30684677). {ECO:0000250|UniProtKB:Q8VIG1, CC ECO:0000269|PubMed:24670762, ECO:0000269|PubMed:27531581, CC ECO:0000269|PubMed:30684677}. CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm CC {ECO:0000269|PubMed:16442230}. CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Nucleus CC {ECO:0000269|PubMed:11741002, ECO:0000269|PubMed:16442230}. CC -!- SUBCELLULAR LOCATION: [Isoform 4]: Cytoplasm CC {ECO:0000269|PubMed:16442230}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Comment=Additional isoforms seem to exist.; CC Name=1; Synonyms=REST1 {ECO:0000303|PubMed:16442230}; CC IsoId=Q13127-1; Sequence=Displayed; CC Name=2; CC IsoId=Q13127-2; Sequence=VSP_022064, VSP_022065; CC Name=3; Synonyms=N4, REST4 {ECO:0000303|PubMed:11779185}; CC IsoId=Q13127-3; Sequence=VSP_022066, VSP_022068; CC Name=4; CC IsoId=Q13127-4; Sequence=VSP_022067; CC -!- TISSUE SPECIFICITY: Expressed in neurons of the prefrontal cortex, in CC hippocampal pyramidal neurons, dentate gyrus granule neurons and CC cerebellar Purkinje and granule neurons (at protein level) CC (PubMed:24670762). Expressed in dopaminergic neurons of the substantia CC nigra (at protein level) (PubMed:30684677). Expressed in neural CC progenitor cells (at protein level) (PubMed:21258371). In patients CC suffering from Alzheimer disease, frontotemporal dementia or dementia CC with Lewy bodies, decreased nuclear levels have been observed in CC neurons of the prefrontal cortex and the hippocampus, but not in CC neurons of the dentate gyrus and cerebellum (at protein level) CC (PubMed:24670762). In patients with Parkinson disease or dementia with CC Lewy bodies, decreased nuclear levels have been observed in CC dopaminergic neurons and in cortical neurons and localization to Lewy CC bodies and pale bodies was detected (at protein level) CC (PubMed:30684677). Expressed at higher levels in weakly invasive breast CC cancer cell lines and at lower levels in highly invasive breast cancer CC lines (at protein level) (PubMed:26053433). Ubiquitous CC (PubMed:8568247). Expressed at higher levels in the tissues of the CC lymphocytic compartment, including spleen, thymus, peripheral blood CC lymphocytes and ovary (PubMed:8568247). {ECO:0000269|PubMed:21258371, CC ECO:0000269|PubMed:24670762, ECO:0000269|PubMed:26053433, CC ECO:0000269|PubMed:30684677, ECO:0000269|PubMed:8568247}. CC -!- DEVELOPMENTAL STAGE: Expression is cell cycle-dependent with decreased CC levels in G2 phase; mediated by proteasomal degradation (at protein CC level) (PubMed:18354482). In aged individuals, increased expression in CC hippocampal CA1, CA3 and CA4 pyramidal neurons and in dentate granule CC cell neurons, but not in the cerebellum (PubMed:24670762). CC {ECO:0000269|PubMed:18354482, ECO:0000269|PubMed:24670762}. CC -!- INDUCTION: Up-regulated by Wnt signaling (PubMed:24670762). Up- CC regulated in the brain of aging individuals but not in Alzheimer CC disease patients (PubMed:24670762). Up-regulated by oxidative stress CC (PubMed:24670762). Down-regulated during neural progenitor cell CC differentiation (PubMed:21258371). {ECO:0000269|PubMed:21258371, CC ECO:0000269|PubMed:24670762}. CC -!- DOMAIN: The C2H2-type zinc finger 5 is required for nuclear CC localization. {ECO:0000269|PubMed:16442230}. CC -!- PTM: O-glycosylated. {ECO:0000250|UniProtKB:Q8VIG1}. CC -!- PTM: Phosphorylated; phosphorylation is required for ubiquitination. CC {ECO:0000269|PubMed:18354482}. CC -!- PTM: Ubiquitinated; ubiquitination is mediated by BTRC and leads to CC proteasomal degradation in G2 phase (PubMed:18354482, PubMed:21258371). CC Ubiquitination increases during neuronal differentiation CC (PubMed:21258371). Deubiquitinated by USP7; leading to its CC stabilization and promoting the maintenance of neural progenitor cells CC (PubMed:21258371). {ECO:0000269|PubMed:18354482, CC ECO:0000269|PubMed:21258371}. CC -!- DISEASE: Wilms tumor 6 (WT6) [MIM:616806]: A pediatric malignancy of CC kidney, and the most common childhood abdominal malignancy. It is CC caused by the uncontrolled multiplication of renal stem, stromal, and CC epithelial cells. {ECO:0000269|PubMed:26551668}. Note=Disease CC susceptibility is associated with variants affecting the gene CC represented in this entry. CC -!- DISEASE: Fibromatosis, gingival, 5 (GINGF5) [MIM:617626]: An autosomal CC dominant form of hereditary gingival fibromatosis, a rare condition CC characterized by a slow, progressive overgrowth of the gingiva. The CC excess gingival tissue can cover part of or the entire crown, and can CC result in diastemas, teeth displacement, or retention of primary or CC impacted teeth. {ECO:0000269|PubMed:28686854}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Note=An intronic variant that affects alternative splicing of CC REST into isoform 3 and inactivation of REST repressor activity is CC associated with progressive hearing loss and deafness. CC {ECO:0000269|PubMed:29961578}. CC -!- DISEASE: Deafness, autosomal dominant, 27 (DFNA27) [MIM:612431]: A form CC of non-syndromic deafness characterized by postlingual, progressive, CC moderate to profound sensorineural hearing loss. CC {ECO:0000269|PubMed:29961578}. Note=The disease may be caused by CC variants affecting the gene represented in this entry. An intronic CC variant that affects alternative splicing of REST and inactivation of CC REST repressor activity fully segregates with deafness in a 3- CC generation family. {ECO:0000269|PubMed:29961578}. CC -!- MISCELLANEOUS: [Isoform 3]: Produced by SRRM4-dependent alternative CC splicing in neurons and inner ear hair cells (By similarity). Lacks the CC four C-terminal zinc fingers and the RCOR1 corepressor interaction site CC found in full length REST isoform 1, which are required for full DNA- CC binding and repressive activity (PubMed:11741002). CC {ECO:0000250|UniProtKB:Q8VIG1, ECO:0000269|PubMed:11741002}. CC -!- CAUTION: [Isoform 3]: Controversial data exists concerning the CC repressor activity of isoform 3. A study showed that isoform 3 exhibits CC weak repressor activity of a NRSE motif-containing reporter construct CC (PubMed:11779185). Another report, however, does not observe any CC isoform 3 transcriptional repressor activity of a NRSE motif-containing CC reporter construct (PubMed:11741002). Controversial data also exists CC regarding the function of isoform 3 on the negative regulation of CC isoform 1. It was shown that isoform 3 negatively regulates the CC repressor activity of isoform 1 by binding to isoform 1, thereby CC preventing its binding to NRSE and leading to derepression of target CC genes (PubMed:11779185). Another study, however, did not observe any CC inhibitory activity of isoform 3 on the isoform 1 transcriptional CC repressor activity (PubMed:11741002). {ECO:0000269|PubMed:11741002, CC ECO:0000269|PubMed:11779185}. CC -!- SEQUENCE CAUTION: CC Sequence=AAA98503.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=AAC50114.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAC50115.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH38985.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; CC Sequence=BAD92987.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/44266/REST"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U22314; AAB17211.1; -; mRNA. DR EMBL; U13877; AAC50114.1; ALT_INIT; mRNA. DR EMBL; U13879; AAC50115.1; ALT_INIT; mRNA. DR EMBL; U22680; AAA98503.1; ALT_FRAME; mRNA. DR EMBL; AB209750; BAD92987.1; ALT_INIT; mRNA. DR EMBL; AC069307; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471057; EAX05517.1; -; Genomic_DNA. DR EMBL; BC038985; AAH38985.1; ALT_SEQ; mRNA. DR EMBL; BC132859; AAI32860.1; -; mRNA. DR EMBL; BC136491; AAI36492.1; -; mRNA. DR CCDS; CCDS3509.1; -. [Q13127-1] DR PIR; A56138; A56138. DR PIR; I38754; I38754. DR PIR; I38755; I38755. DR RefSeq; NP_001180437.1; NM_001193508.2. [Q13127-1] DR RefSeq; NP_001350382.1; NM_001363453.3. [Q13127-1] DR RefSeq; NP_005603.3; NM_005612.4. [Q13127-1] DR PDB; 2CZY; NMR; -; B=43-57. DR PDB; 6DU2; X-ray; 2.50 A; C/D=858-869. DR PDB; 6DU3; X-ray; 2.58 A; C/D=858-869. DR PDBsum; 2CZY; -. DR PDBsum; 6DU2; -. DR PDBsum; 6DU3; -. DR AlphaFoldDB; Q13127; -. DR BMRB; Q13127; -. DR SMR; Q13127; -. DR BioGRID; 111910; 267. DR CORUM; Q13127; -. DR DIP; DIP-35264N; -. DR FunCoup; Q13127; 4087. DR IntAct; Q13127; 20. DR MINT; Q13127; -. DR STRING; 9606.ENSP00000311816; -. DR GlyGen; Q13127; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q13127; -. DR PhosphoSitePlus; Q13127; -. DR BioMuta; REST; -. DR DMDM; 296452989; -. DR jPOST; Q13127; -. DR MassIVE; Q13127; -. DR PaxDb; 9606-ENSP00000311816; -. DR PeptideAtlas; Q13127; -. DR ProteomicsDB; 59175; -. [Q13127-1] DR ProteomicsDB; 59176; -. [Q13127-2] DR ProteomicsDB; 59177; -. [Q13127-3] DR ProteomicsDB; 59178; -. [Q13127-4] DR Pumba; Q13127; -. DR Antibodypedia; 1755; 291 antibodies from 38 providers. DR DNASU; 5978; -. DR Ensembl; ENST00000309042.12; ENSP00000311816.7; ENSG00000084093.20. [Q13127-1] DR Ensembl; ENST00000675105.1; ENSP00000502313.1; ENSG00000084093.20. [Q13127-1] DR GeneID; 5978; -. DR KEGG; hsa:5978; -. DR MANE-Select; ENST00000309042.12; ENSP00000311816.7; NM_005612.5; NP_005603.3. DR UCSC; uc003hch.4; human. [Q13127-1] DR AGR; HGNC:9966; -. DR ClinPGx; PA34334; -. DR CTD; 5978; -. DR DisGeNET; 5978; -. DR GeneCards; REST; -. DR HGNC; HGNC:9966; REST. DR HPA; ENSG00000084093; Low tissue specificity. DR MalaCards; REST; -. DR MIM; 600571; gene. DR MIM; 612431; phenotype. DR MIM; 616806; phenotype. DR MIM; 617626; phenotype. DR OpenTargets; ENSG00000084093; -. DR Orphanet; 2024; Hereditary gingival fibromatosis. DR Orphanet; 654; Nephroblastoma. DR VEuPathDB; HostDB:ENSG00000084093; -. DR eggNOG; KOG1721; Eukaryota. DR GeneTree; ENSGT00940000155341; -. DR HOGENOM; CLU_009801_2_0_1; -. DR InParanoid; Q13127; -. DR OrthoDB; 427030at2759; -. DR PAN-GO; Q13127; 7 GO annotations based on evolutionary models. DR PhylomeDB; Q13127; -. DR PathwayCommons; Q13127; -. DR Reactome; R-HSA-3214815; HDACs deacetylate histones. DR Reactome; R-HSA-8943724; Regulation of PTEN gene transcription. DR Reactome; R-HSA-9031628; NGF-stimulated transcription. DR Reactome; R-HSA-9679191; Potential therapeutics for SARS. DR Reactome; R-HSA-9768777; Regulation of NPAS4 gene transcription. DR SignaLink; Q13127; -. DR SIGNOR; Q13127; -. DR Agora; ENSG00000084093; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 5978; 49 hits in 1187 CRISPR screens. DR ChiTaRS; REST; human. DR GeneWiki; RE1-silencing_transcription_factor; -. DR GenomeRNAi; 5978; -. DR Pharos; Q13127; Tbio. DR PRO; PR:Q13127; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; Q13127; protein. DR Bgee; ENSG00000084093; Expressed in primordial germ cell in gonad and 209 other cell types or tissues. DR ExpressionAtlas; Q13127; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0017053; C:transcription repressor complex; IDA:UniProtKB. DR GO; GO:0003682; F:chromatin binding; ISS:UniProtKB. DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB. DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; ISS:UniProtKB. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:UniProtKB. DR GO; GO:0000979; F:RNA polymerase II core promoter sequence-specific DNA binding; IEA:Ensembl. DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:UniProtKB. DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW. DR GO; GO:0060088; P:auditory receptor cell stereocilium organization; ISS:UniProtKB. DR GO; GO:0060379; P:cardiac muscle cell myoblast differentiation; ISS:UniProtKB. DR GO; GO:0071257; P:cellular response to electrical stimulus; IMP:UniProtKB. DR GO; GO:0071385; P:cellular response to glucocorticoid stimulus; IDA:UniProtKB. DR GO; GO:0033554; P:cellular response to stress; IEA:Ensembl. DR GO; GO:0006338; P:chromatin remodeling; ISS:UniProtKB. DR GO; GO:0050910; P:detection of mechanical stimulus involved in sensory perception of sound; ISS:UniProtKB. DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IEA:Ensembl. DR GO; GO:0043922; P:host-mediated suppression of viral transcription; IDA:UniProtKB. DR GO; GO:0099563; P:modification of synaptic structure; ISS:UniProtKB. DR GO; GO:0032348; P:negative regulation of aldosterone biosynthetic process; IMP:UniProtKB. DR GO; GO:2000798; P:negative regulation of amniotic stem cell differentiation; IMP:UniProtKB. DR GO; GO:0045955; P:negative regulation of calcium ion-dependent exocytosis; ISS:UniProtKB. DR GO; GO:2000065; P:negative regulation of cortisol biosynthetic process; IMP:UniProtKB. DR GO; GO:2000706; P:negative regulation of dense core granule biogenesis; ISS:UniProtKB. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0010629; P:negative regulation of gene expression; ISS:UniProtKB. DR GO; GO:0046676; P:negative regulation of insulin secretion; IMP:UniProtKB. DR GO; GO:2000740; P:negative regulation of mesenchymal stem cell differentiation; IMP:UniProtKB. DR GO; GO:1902894; P:negative regulation of miRNA transcription; IMP:BHF-UCL. DR GO; GO:0050768; P:negative regulation of neurogenesis; ISS:UniProtKB. DR GO; GO:0045665; P:negative regulation of neuron differentiation; IDA:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0050877; P:nervous system process; IMP:UniProtKB. DR GO; GO:0050885; P:neuromuscular process controlling balance; ISS:UniProtKB. DR GO; GO:0097150; P:neuronal stem cell population maintenance; ISS:UniProtKB. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0010628; P:positive regulation of gene expression; ISS:UniProtKB. DR GO; GO:0045666; P:positive regulation of neuron differentiation; ISS:UniProtKB. DR GO; GO:0043068; P:positive regulation of programmed cell death; ISS:UniProtKB. DR GO; GO:1902459; P:positive regulation of stem cell population maintenance; IDA:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IBA:GO_Central. DR GO; GO:0000381; P:regulation of alternative mRNA splicing, via spliceosome; ISS:UniProtKB. DR GO; GO:0006355; P:regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0045667; P:regulation of osteoblast differentiation; ISS:UniProtKB. DR GO; GO:0001666; P:response to hypoxia; IDA:UniProtKB. DR GO; GO:0002931; P:response to ischemia; ISS:UniProtKB. DR GO; GO:0035019; P:somatic stem cell population maintenance; ISS:UniProtKB. DR FunFam; 3.30.160.60:FF:002187; RE1-silencing transcription factor; 1. DR FunFam; 3.30.160.60:FF:000448; RE1-silencing transcription factor A; 1. DR FunFam; 3.30.160.60:FF:000662; RE1-silencing transcription factor A; 1. DR FunFam; 3.30.160.60:FF:000805; RE1-silencing transcription factor B; 1. DR FunFam; 3.30.160.60:FF:000952; RE1-silencing transcription factor B; 1. DR Gene3D; 3.30.160.60; Classic Zinc Finger; 5. DR IDEAL; IID00169; -. DR InterPro; IPR057281; Zfn-C2H2_REST. DR InterPro; IPR050688; Zinc_finger/UBP_domain. DR InterPro; IPR036236; Znf_C2H2_sf. DR InterPro; IPR013087; Znf_C2H2_type. DR PANTHER; PTHR24403:SF102; RE1-SILENCING TRANSCRIPTION FACTOR; 1. DR PANTHER; PTHR24403; ZINC FINGER PROTEIN; 1. DR Pfam; PF00096; zf-C2H2; 1. DR Pfam; PF24540; zf-C2H2_REST; 1. DR SMART; SM00355; ZnF_C2H2; 9. DR SUPFAM; SSF57667; beta-beta-alpha zinc fingers; 3. DR PROSITE; PS00028; ZINC_FINGER_C2H2_1; 1. DR PROSITE; PS50157; ZINC_FINGER_C2H2_2; 6. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasm; Deafness; Disease variant; KW Metal-binding; Non-syndromic deafness; Nucleus; Phosphoprotein; KW Proteomics identification; Reference proteome; Repeat; Repressor; KW Transcription; Transcription regulation; Ubl conjugation; Zinc; KW Zinc-finger. FT CHAIN 1..1097 FT /note="RE1-silencing transcription factor" FT /id="PRO_0000269547" FT ZN_FING 159..181 FT /note="C2H2-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 216..238 FT /note="C2H2-type 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 248..270 FT /note="C2H2-type 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 276..298 FT /note="C2H2-type 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 304..326 FT /note="C2H2-type 5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 332..355 FT /note="C2H2-type 6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 361..383 FT /note="C2H2-type 7" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 389..412 FT /note="C2H2-type 8" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 1060..1082 FT /note="C2H2-type 9" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT REGION 32..122 FT /note="Interaction with SIN3A" FT /evidence="ECO:0000269|PubMed:10734093" FT REGION 43..57 FT /note="Interaction with SIN3B" FT /evidence="ECO:0000269|PubMed:16288918" FT REGION 83..103 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 127..159 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 145..418 FT /note="Interaction with ZFP90" FT /evidence="ECO:0000269|PubMed:21284946" FT REGION 201..212 FT /note="Required for binding to the neuron-restrictive FT silencer element" FT /evidence="ECO:0000250|UniProtKB:Q8VIG1" FT REGION 452..642 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 774..837 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 853..938 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 961..1049 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1009..1087 FT /note="Interaction with RCOR1" FT /evidence="ECO:0000269|PubMed:10449787" FT COMPBIAS 86..96 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 452..479 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 480..490 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 495..504 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 559..570 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 577..593 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 803..836 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 913..930 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 864 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:23186163" FT MOD_RES 971 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O54963" FT VAR_SEQ 301..313 FT /note="ERPYKCELCPYSS -> KRSFLVHKFSSLF (in isoform 2)" FT /evidence="ECO:0000303|PubMed:7871435" FT /id="VSP_022064" FT VAR_SEQ 304..326 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000305" FT /id="VSP_022067" FT VAR_SEQ 314..1097 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:7871435" FT /id="VSP_022065" FT VAR_SEQ 329 FT /note="E -> W (in isoform 3)" FT /evidence="ECO:0000305" FT /id="VSP_022066" FT VAR_SEQ 330..1097 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000305" FT /id="VSP_022068" FT VARIANT 160 FT /note="R -> P (in WT6; inhibits transcriptional repression FT activity)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076333" FT VARIANT 290 FT /note="N -> Y (in WT6; inhibits transcriptional repression FT activity)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076334" FT VARIANT 322 FT /note="H -> R (in WT6; inhibits transcriptional repression FT activity; dbSNP:rs869025312)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076335" FT VARIANT 412 FT /note="H -> Q (in WT6)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076336" FT VARIANT 437..1097 FT /note="Missing (in GINGF5)" FT /evidence="ECO:0000269|PubMed:28686854" FT /id="VAR_079529" FT VARIANT 626 FT /note="V -> I (in dbSNP:rs2228991)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_029795" FT VARIANT 692 FT /note="E -> D (in dbSNP:rs2227902)" FT /id="VAR_029796" FT VARIANT 762 FT /note="K -> Q (in dbSNP:rs2227903)" FT /id="VAR_029797" FT VARIANT 797 FT /note="P -> L (in dbSNP:rs3796529)" FT /evidence="ECO:0000269|PubMed:8568247" FT /id="VAR_029798" FT MUTAGEN 91 FT /note="E->G: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 313 FT /note="S->A: Lack of deubiquitination by USP7." FT /evidence="ECO:0000269|PubMed:21258371" FT MUTAGEN 420 FT /note="M->T: Inhibits transcriptional repression activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 512..522 FT /note="KFSKTKKSKRK->AFSKTADSMDA: No effect on nuclear FT localization." FT /evidence="ECO:0000269|PubMed:16442230" FT MUTAGEN 512..522 FT /note="KFSKTKKSKRK->GS: Reduced nuclear localization." FT /evidence="ECO:0000269|PubMed:16442230" FT MUTAGEN 512..522 FT /note="Missing: No effect on nuclear localization." FT /evidence="ECO:0000269|PubMed:16442230" FT MUTAGEN 593 FT /note="S->N: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 642 FT /note="A->T: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 918 FT /note="H->Y: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 1009..1013 FT /note="EGIHS->AGIHA: Loss of interaction with BTRC. Reduced FT ubiquitination. Decreased proteasomal degradation in G2. FT Decreased average time from nuclear envelope breakdown to FT anaphase onset. Increased number of lagging chromosomes and FT chromosome bridges in anaphase and prematurely separated FT sister chromatids. Reduced MAD2 levels." FT /evidence="ECO:0000269|PubMed:18354482" FT MUTAGEN 1009 FT /note="E->A: Loss of interaction with BTRC." FT /evidence="ECO:0000269|PubMed:18354482" FT MUTAGEN 1013 FT /note="S->A: Loss of interaction with BTRC." FT /evidence="ECO:0000269|PubMed:18354482" FT MUTAGEN 1042 FT /note="S->A: No impact on deubiquitination by USP7." FT /evidence="ECO:0000269|PubMed:21258371" FT CONFLICT 295 FT /note="V -> L (in Ref. 2; AAC50114)" FT /evidence="ECO:0000305" FT CONFLICT 596..599 FT /note="PQKE -> SRNS (in Ref. 2; AAC50115)" FT /evidence="ECO:0000305" FT CONFLICT 630 FT /note="P -> L (in Ref. 1; AAB17211)" FT /evidence="ECO:0000305" FT HELIX 44..55 FT /evidence="ECO:0007829|PDB:2CZY" SQ SEQUENCE 1097 AA; 121872 MW; EBC652EED19CA161 CRC64; MATQVMGQSS GGGGLFTSSG NIGMALPNDM YDLHDLSKAE LAAPQLIMLA NVALTGEVNG SCCDYLVGEE RQMAELMPVG DNNFSDSEEG EGLEESADIK GEPHGLENME LRSLELSVVE PQPVFEASGA PDIYSSNKDL PPETPGAEDK GKSSKTKPFR CKPCQYEAES EEQFVHHIRV HSAKKFFVEE SAEKQAKARE SGSSTAEEGD FSKGPIRCDR CGYNTNRYDH YTAHLKHHTR AGDNERVYKC IICTYTTVSE YHWRKHLRNH FPRKVYTCGK CNYFSDRKNN YVQHVRTHTG ERPYKCELCP YSSSQKTHLT RHMRTHSGEK PFKCDQCSYV ASNQHEVTRH ARQVHNGPKP LNCPHCDYKT ADRSNFKKHV ELHVNPRQFN CPVCDYAASK KCNLQYHFKS KHPTCPNKTM DVSKVKLKKT KKREADLPDN ITNEKTEIEQ TKIKGDVAGK KNEKSVKAEK RDVSKEKKPS NNVSVIQVTT RTRKSVTEVK EMDVHTGSNS EKFSKTKKSK RKLEVDSHSL HGPVNDEESS TKKKKKVESK SKNNSQEVPK GDSKVEENKK QNTCMKKSTK KKTLKNKSSK KSSKPPQKEP VEKGSAQMDP PQMGPAPTEA VQKGPVQVEP PPPMEHAQME GAQIRPAPDE PVQMEVVQEG PAQKELLPPV EPAQMVGAQI VLAHMELPPP METAQTEVAQ MGPAPMEPAQ MEVAQVESAP MQVVQKEPVQ MELSPPMEVV QKEPVQIELS PPMEVVQKEP VKIELSPPIE VVQKEPVQME LSPPMGVVQK EPAQREPPPP REPPLHMEPI SKKPPLRKDK KEKSNMQSER ARKEQVLIEV GLVPVKDSWL LKESVSTEDL SPPSPPLPKE NLREEASGDQ KLLNTGEGNK EAPLQKVGAE EADESLPGLA ANINESTHIS SSGQNLNTPE GETLNGKHQT DSIVCEMKMD TDQNTRENLT GINSTVEEPV SPMLPPSAVE EREAVSKTAL ASPPATMAAN ESQEIDEDEG IHSHEGSDLS DNMSEGSDDS GLHGARPVPQ ESSRKNAKEA LAVKAAKGDF VCIFCDRSFR KGKDYSKHLN RHLVNVYYLE EAAQGQE // ID RN146_HUMAN Reviewed; 359 AA. AC Q9NTX7; E1P572; Q6FIB2; Q7L8H4; Q96K03; Q96T06; Q9NTX6; DT 01-MAR-2005, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-2000, sequence version 1. DT 28-JAN-2026, entry version 193. DE RecName: Full=E3 ubiquitin-protein ligase RNF146; DE EC=2.3.2.27; DE AltName: Full=Dactylidin; DE AltName: Full=Iduna; DE AltName: Full=RING finger protein 146; DE AltName: Full=RING-type E3 ubiquitin transferase RNF146 {ECO:0000305}; GN Name=RNF146; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND SUBCELLULAR LOCATION. RC TISSUE=Brain; RX PubMed=15813938; DOI=10.1111/j.1460-9568.2005.03977.x; RA von Rotz R.C., Kins S., Hipfel R., von der Kammer H., Nitsch R.M.; RT "The novel cytosolic RING finger protein dactylidin is up-regulated in RT brains of patients with Alzheimer's disease."; RL Eur. J. Neurosci. 21:1289-1298(2005). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Testis; RX PubMed=11230166; DOI=10.1101/gr.gr1547r; RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S., RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J., RA Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W., RA Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B., RA Klein M., Poustka A.; RT "Towards a catalog of human genes and proteins: sequencing and analysis of RT 500 novel complete protein coding human cDNAs."; RL Genome Res. 11:422-435(2001). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Placenta, and Teratocarcinoma; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Eye; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP POSSIBLE INVOLVEMENT IN BREAST CANCER. RX PubMed=18326623; DOI=10.1073/pnas.0800441105; RA Gold B., Kirchhoff T., Stefanov S., Lautenberger J., Viale A., Garber J., RA Friedman E., Narod S., Olshen A.B., Gregersen P., Kosarin K., Olsh A., RA Bergeron J., Ellis N.A., Klein R.J., Clark A.G., Norton L., Dean M., RA Boyd J., Offit K.; RT "Genome-wide association study provides evidence for a breast cancer risk RT locus at 6q22.33."; RL Proc. Natl. Acad. Sci. U.S.A. 105:4340-4345(2008). RN [9] RP POSSIBLE INVOLVEMENT IN BREAST CANCER. RX PubMed=19690183; DOI=10.1158/1055-9965.epi-09-0151; RA Kirchhoff T., Chen Z.Q., Gold B., Pal P., Gaudet M.M., Kosarin K., RA Levine D.A., Gregersen P., Spencer S., Harlan M., Robson M., Klein R.J., RA Hudis C.A., Norton L., Dean M., Offit K.; RT "The 6q22.33 locus and breast cancer susceptibility."; RL Cancer Epidemiol. Biomarkers Prev. 18:2468-2475(2009). RN [10] RP POSSIBLE INVOLVEMENT IN BREAST CANCER. RX PubMed=19517271; DOI=10.1007/s10689-009-9255-7; RA Menachem T.D., Laitman Y., Kaufman B., Friedman E.; RT "The RNF146 and ECHDC1 genes as candidates for inherited breast and ovarian RT cancer in Jewish Ashkenazi women."; RL Fam. Cancer 8:399-402(2009). RN [11] RP POSSIBLE INVOLVEMENT IN BREAST CANCER. RX PubMed=21445572; DOI=10.1007/s10549-011-1459-5; RA Peng S., Lu B., Ruan W., Zhu Y., Sheng H., Lai M.; RT "Genetic polymorphisms and breast cancer risk: evidence from meta-analyses, RT pooled analyses, and genome-wide association studies."; RL Breast Cancer Res. Treat. 127:309-324(2011). RN [12] RP FUNCTION, PATHWAY, DOMAIN WWE, UBIQUITINATION, INTERACTION WITH AXIN1; RP AXIN2; CASC3 AND BLZF1, AND MUTAGENESIS OF ARG-163. RX PubMed=21478859; DOI=10.1038/ncb2222; RA Zhang Y., Liu S., Mickanin C., Feng Y., Charlat O., Michaud G.A., RA Schirle M., Shi X., Hild M., Bauer A., Myer V.E., Finan P.M., Porter J.A., RA Huang S.M., Cong F.; RT "RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin RT degradation and Wnt signalling."; RL Nat. Cell Biol. 13:623-629(2011). RN [13] RP FUNCTION IN NEUROPROTECTION. RX PubMed=21602803; DOI=10.1038/nm.2387; RA Andrabi S.A., Kang H.C., Haince J.F., Lee Y.I., Zhang J., Chi Z., RA West A.B., Koehler R.C., Poirier G.G., Dawson T.M., Dawson V.L.; RT "Iduna protects the brain from glutamate excitotoxicity and stroke by RT interfering with poly(ADP-ribose) polymer-induced cell death."; RL Nat. Med. 17:692-699(2011). RN [14] RP FUNCTION IN WNT SIGNALING, INTERACTION WITH AXIN1; DDB1; DHX15; IQGAP1; RP LRPPRC; PARP1; PARP2; PRKDC; RUVBL2; TNKS1 AND TNKS2, UBIQUITINATION, RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF HIS-54 AND TRP-106. RX PubMed=21799911; DOI=10.1371/journal.pone.0022595; RA Callow M.G., Tran H., Phu L., Lau T., Lee J., Sandoval W.N., Liu P.S., RA Bheddah S., Tao J., Lill J.R., Hongo J.A., Davis D., Kirkpatrick D.S., RA Polakis P., Costa M.; RT "Ubiquitin ligase RNF146 regulates tankyrase and Axin to promote Wnt RT signaling."; RL PLoS ONE 6:E22595-E22595(2011). RN [15] RP FUNCTION IN DNA DAMAGE RESPONSE, HOMOOLIGOMERIZATION, INTERACTION WITH RP H1-2; IPO7; LIG3; NCL; PARP1; XRCC1; XRCC5 AND XRCC6, SUBCELLULAR LOCATION, RP AND AUTOUBIQUITINATION AT LYS-85; LYS-95; LYS-131 AND LYS-176. RX PubMed=21825151; DOI=10.1073/pnas.1108799108; RA Kang H.C., Lee Y.I., Shin J.H., Andrabi S.A., Chi Z., Gagne J.P., Lee Y., RA Ko H.S., Lee B.D., Poirier G.G., Dawson V.L., Dawson T.M.; RT "Iduna is a poly(ADP-ribose) (PAR)-dependent E3 ubiquitin ligase that RT regulates DNA damage."; RL Proc. Natl. Acad. Sci. U.S.A. 108:14103-14108(2011). RN [16] RP STRUCTURE BY NMR OF 24-84. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of the RING domain of the human RING finger protein RT 146."; RL Submitted (JUN-2006) to the PDB data bank. RN [17] RP X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 100-184 IN COMPLEX WITH RP ISO-ADP-RIBOSE, FUNCTION, AND MUTAGENESIS OF TYR-108; ARG-111; TRP-115; RP TYR-145; GLN-154; ARG-164 AND LYS-176. RX PubMed=22267412; DOI=10.1101/gad.182618.111; RA Wang Z., Michaud G.A., Cheng Z., Zhang Y., Hinds T.R., Fan E., Cong F., RA Xu W.; RT "Recognition of the iso-ADP-ribose moiety in poly(ADP-ribose) by WWE RT domains suggests a general mechanism for poly(ADP-ribosyl)ation-dependent RT ubiquitination."; RL Genes Dev. 26:235-240(2012). CC -!- FUNCTION: E3 ubiquitin-protein ligase that specifically binds poly-ADP- CC ribosylated (PARsylated) proteins and mediates their ubiquitination and CC subsequent degradation (PubMed:21478859, PubMed:21799911, CC PubMed:22267412). May regulate many important biological processes, CC such as cell survival and DNA damage response (PubMed:21825151, CC PubMed:22267412). Acts as an activator of the Wnt signaling pathway by CC mediating the ubiquitination of PARsylated AXIN1 and AXIN2, 2 key CC components of the beta-catenin destruction complex (PubMed:21478859, CC PubMed:21799911). Acts in cooperation with tankyrase proteins (TNKS and CC TNKS2), which mediate PARsylation of target proteins AXIN1, AXIN2, CC BLZF1, CASC3, TNKS and TNKS2 (PubMed:21799911). Recognizes and binds CC tankyrase-dependent PARsylated proteins via its WWE domain and mediates CC their ubiquitination, leading to their degradation (PubMed:21799911). CC Different ubiquitin linkage types have been observed: TNKS2 undergoes CC ubiquitination at 'Lys-48' and 'Lys-63', while AXIN1 is only CC ubiquitinated at 'Lys-48' (PubMed:21799911). May regulate TNKS and CC TNKS2 subcellular location, preventing aggregation at a centrosomal CC location (PubMed:21799911). Neuroprotective protein (PubMed:21602803). CC Protects the brain against N-methyl-D-aspartate (NMDA) receptor- CC mediated glutamate excitotoxicity and ischemia, by interfering with CC PAR-induced cell death, called parthanatos (By similarity). Prevents CC nuclear translocation of AIFM1 in a PAR-binding dependent manner (By CC similarity). Does not affect PARP1 activation (By similarity). Protects CC against cell death induced by DNA damaging agents, such as N-methyl-N- CC nitro-N-nitrosoguanidine (MNNG) and rescues cells from G1 arrest (By CC similarity). Promotes cell survival after gamma-irradiation CC (PubMed:21825151). Facilitates DNA repair (PubMed:21825151). CC {ECO:0000250|UniProtKB:Q9CZW6, ECO:0000269|PubMed:21478859, CC ECO:0000269|PubMed:21602803, ECO:0000269|PubMed:21799911, CC ECO:0000269|PubMed:21825151, ECO:0000269|PubMed:22267412}. CC -!- CATALYTIC ACTIVITY: CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; CC EC=2.3.2.27; CC -!- PATHWAY: Protein modification; protein ubiquitination. CC {ECO:0000269|PubMed:21478859}. CC -!- SUBUNIT: Can form homooligomers. Interacts with PARsylated AXIN1, CC AXIN2, BLZF1, CASC3, H1-2, IPO7, LIG3, NCL, PARP1, XRCC1, XRCC5 and CC XRCC6. Interacts with DDB1, DHX15, IQGAP1, LRPPRC, PARP2, PRKDC, CC RUVBL2, TNKS1 and TNKS2. Binding often leads to interactor CC ubiquitination, in the presence of the appropriate E1 and E2 enzymes, CC and proteasomal degradation. {ECO:0000269|PubMed:21478859, CC ECO:0000269|PubMed:21799911, ECO:0000269|PubMed:21825151, CC ECO:0000269|PubMed:22267412}. CC -!- INTERACTION: CC Q9NTX7; Q12959: DLG1; NbExp=4; IntAct=EBI-722397, EBI-357481; CC Q9NTX7; P78352: DLG4; NbExp=2; IntAct=EBI-722397, EBI-80389; CC Q9NTX7; Q8N6L0: KASH5; NbExp=3; IntAct=EBI-722397, EBI-749265; CC Q9NTX7; Q8TBB1: LNX1; NbExp=2; IntAct=EBI-722397, EBI-739832; CC Q9NTX7; Q86UL8: MAGI2; NbExp=4; IntAct=EBI-722397, EBI-311035; CC Q9NTX7; Q5TCQ9: MAGI3; NbExp=2; IntAct=EBI-722397, EBI-310506; CC Q9NTX7; P09874: PARP1; NbExp=5; IntAct=EBI-722397, EBI-355676; CC Q9NTX7; Q8NI35: PATJ; NbExp=3; IntAct=EBI-722397, EBI-724390; CC Q9NTX7; Q14160: SCRIB; NbExp=3; IntAct=EBI-722397, EBI-357345; CC Q9NTX7; O95271: TNKS; NbExp=7; IntAct=EBI-722397, EBI-1105254; CC Q9NTX7; Q12933: TRAF2; NbExp=3; IntAct=EBI-722397, EBI-355744; CC Q9NTX7; Q9UGJ1: TUBGCP4; NbExp=3; IntAct=EBI-722397, EBI-1052544; CC Q9NTX7-2; Q8N6L0: KASH5; NbExp=7; IntAct=EBI-11750630, EBI-749265; CC Q9NTX7-2; Q9BU61: NDUFAF3; NbExp=3; IntAct=EBI-11750630, EBI-2114801; CC Q9NTX7-2; P49821: NDUFV1; NbExp=3; IntAct=EBI-11750630, EBI-748312; CC Q9NTX7-2; Q12933: TRAF2; NbExp=3; IntAct=EBI-11750630, EBI-355744; CC Q9NTX7-2; O76024: WFS1; NbExp=3; IntAct=EBI-11750630, EBI-720609; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol. Nucleus. Note=Translocates to CC the nucleus after DNA damage, such as laser-induced DNA breaks, and CC concentrates at DNA breaks. This translocation requires PARP1 CC activation and PAR-binding. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q9NTX7-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9NTX7-2; Sequence=VSP_012968; CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. Up-regulated in brains from CC patients with Alzheimer disease. CC -!- DOMAIN: The WWE domain mediates non-covalent PAR-binding. CC {ECO:0000269|PubMed:21478859}. CC -!- PTM: Ubiquitinated; autoubiquitinated. Polyubiquitinated in the CC presence of UBE2D1, UBE2D2 and UBE2D3. Multimonoubiquitinated in the CC presence of UBE2E1. Not ubiquitinated in the presence of UBE2H, CDC34, CC UBE2L3, UBE2L6, nor UBE2C. In the absence of PAR, autoubiquitination CC occurs on Lys-85, Lys-95 and Lys-176 via 'Lys-11' and 'Lys-48' CC ubiquitin linkages. In the presence of PAR, Lys-131 and Lys-176 are CC ubiquitinated via 'Lys-6', 'Lys-33' and 'Lys-48' ubiquitin linkages. CC Autoubiquitination is enhanced upon PAR-binding. CC {ECO:0000269|PubMed:21478859, ECO:0000269|PubMed:21799911, CC ECO:0000269|PubMed:21825151}. CC -!- DISEASE: Note=Defects in RNF146 are a cause of susceptibility to breast CC cancer. CC -!- MISCELLANEOUS: Was named dactylidin after the Greek term 'daktylidi' CC for ring, 'the thing around the finger' (PubMed:15813938). Was named CC Iduna after the Norse goddess of protection and eternal youth CC (PubMed:21602803). {ECO:0000305|PubMed:15813938, CC ECO:0000305|PubMed:21602803}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AJ315122; CAC85986.1; -; mRNA. DR EMBL; AL136829; CAB66763.1; -; mRNA. DR EMBL; AK027558; BAB55196.1; -; mRNA. DR EMBL; AK027436; BAB55108.1; -; mRNA. DR EMBL; AK027776; BAB55359.1; -; mRNA. DR EMBL; CR533514; CAG38545.1; -; mRNA. DR EMBL; AL109939; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471051; EAW48109.1; -; Genomic_DNA. DR EMBL; CH471051; EAW48111.1; -; Genomic_DNA. DR EMBL; BC008235; AAH08235.1; -; mRNA. DR CCDS; CCDS5136.1; -. [Q9NTX7-2] DR CCDS; CCDS56449.1; -. [Q9NTX7-1] DR RefSeq; NP_001229773.1; NM_001242844.2. [Q9NTX7-2] DR RefSeq; NP_001229774.1; NM_001242845.2. [Q9NTX7-2] DR RefSeq; NP_001229775.1; NM_001242846.2. [Q9NTX7-2] DR RefSeq; NP_001229776.1; NM_001242847.2. [Q9NTX7-2] DR RefSeq; NP_001229777.1; NM_001242848.2. [Q9NTX7-2] DR RefSeq; NP_001229778.1; NM_001242849.2. [Q9NTX7-1] DR RefSeq; NP_001229779.1; NM_001242850.2. [Q9NTX7-1] DR RefSeq; NP_001229780.1; NM_001242851.1. [Q9NTX7-1] DR RefSeq; NP_001229781.1; NM_001242852.2. [Q9NTX7-2] DR RefSeq; NP_112225.2; NM_030963.3. [Q9NTX7-2] DR RefSeq; XP_011534463.1; XM_011536161.4. [Q9NTX7-2] DR RefSeq; XP_011534465.1; XM_011536163.4. [Q9NTX7-2] DR RefSeq; XP_011534466.1; XM_011536164.4. [Q9NTX7-2] DR RefSeq; XP_016866825.1; XM_017011336.3. [Q9NTX7-1] DR RefSeq; XP_047275342.1; XM_047419386.1. [Q9NTX7-2] DR RefSeq; XP_047275343.1; XM_047419387.1. [Q9NTX7-2] DR RefSeq; XP_047275344.1; XM_047419388.1. [Q9NTX7-2] DR RefSeq; XP_047275345.1; XM_047419389.1. [Q9NTX7-2] DR RefSeq; XP_054212474.1; XM_054356499.1. [Q9NTX7-1] DR RefSeq; XP_054212475.1; XM_054356500.1. [Q9NTX7-2] DR RefSeq; XP_054212476.1; XM_054356501.1. [Q9NTX7-2] DR RefSeq; XP_054212477.1; XM_054356502.1. [Q9NTX7-2] DR RefSeq; XP_054212478.1; XM_054356503.1. [Q9NTX7-2] DR RefSeq; XP_054212479.1; XM_054356504.1. [Q9NTX7-2] DR RefSeq; XP_054212480.1; XM_054356505.1. [Q9NTX7-2] DR RefSeq; XP_054212481.1; XM_054356506.1. [Q9NTX7-2] DR PDB; 2D8T; NMR; -; A=27-84. DR PDB; 3V3L; X-ray; 1.65 A; A/B=100-184. DR PDB; 6CF6; X-ray; 1.93 A; C/D=191-203. DR PDBsum; 2D8T; -. DR PDBsum; 3V3L; -. DR PDBsum; 6CF6; -. DR AlphaFoldDB; Q9NTX7; -. DR SMR; Q9NTX7; -. DR BioGRID; 123598; 76. DR DIP; DIP-52730N; -. DR FunCoup; Q9NTX7; 2943. DR IntAct; Q9NTX7; 92. DR MINT; Q9NTX7; -. DR STRING; 9606.ENSP00000357297; -. DR GlyCosmos; Q9NTX7; 1 site, 1 glycan. DR GlyGen; Q9NTX7; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q9NTX7; -. DR PhosphoSitePlus; Q9NTX7; -. DR BioMuta; RNF146; -. DR DMDM; 60390653; -. DR jPOST; Q9NTX7; -. DR MassIVE; Q9NTX7; -. DR PaxDb; 9606-ENSP00000357297; -. DR PeptideAtlas; Q9NTX7; -. DR ProteomicsDB; 82642; -. [Q9NTX7-1] DR ProteomicsDB; 82643; -. [Q9NTX7-2] DR Pumba; Q9NTX7; -. DR Antibodypedia; 19579; 66 antibodies from 17 providers. DR DNASU; 81847; -. DR Ensembl; ENST00000368314.6; ENSP00000357297.1; ENSG00000118518.18. [Q9NTX7-1] DR Ensembl; ENST00000608991.5; ENSP00000477168.1; ENSG00000118518.18. [Q9NTX7-2] DR Ensembl; ENST00000610153.1; ENSP00000476814.1; ENSG00000118518.18. [Q9NTX7-1] DR GeneID; 81847; -. DR KEGG; hsa:81847; -. DR MANE-Select; ENST00000368314.6; ENSP00000357297.1; NM_001242850.2; NP_001229779.1. DR UCSC; uc003qav.4; human. [Q9NTX7-1] DR AGR; HGNC:21336; -. DR ClinPGx; PA134910489; -. DR CTD; 81847; -. DR DisGeNET; 81847; -. DR GeneCards; RNF146; -. DR HGNC; HGNC:21336; RNF146. DR HPA; ENSG00000118518; Low tissue specificity. DR MIM; 612137; gene. DR OpenTargets; ENSG00000118518; -. DR VEuPathDB; HostDB:ENSG00000118518; -. DR eggNOG; KOG0824; Eukaryota. DR GeneTree; ENSGT00390000000358; -. DR HOGENOM; CLU_067425_0_0_1; -. DR InParanoid; Q9NTX7; -. DR OMA; KMAGCGE; -. DR OrthoDB; 10065815at2759; -. DR PAN-GO; Q9NTX7; 5 GO annotations based on evolutionary models. DR PhylomeDB; Q9NTX7; -. DR PathwayCommons; Q9NTX7; -. DR Reactome; R-HSA-201681; TCF dependent signaling in response to WNT. DR Reactome; R-HSA-4641257; Degradation of AXIN. DR Reactome; R-HSA-5689880; Ub-specific processing proteases. DR Reactome; R-HSA-8948751; Regulation of PTEN stability and activity. DR SignaLink; Q9NTX7; -. DR SIGNOR; Q9NTX7; -. DR UniPathway; UPA00143; -. DR Agora; ENSG00000118518; -. DR BioGRID-ORCS; 81847; 44 hits in 1216 CRISPR screens. DR ChiTaRS; RNF146; human. DR EvolutionaryTrace; Q9NTX7; -. DR GeneWiki; RNF146; -. DR GenomeRNAi; 81847; -. DR Pharos; Q9NTX7; Tbio. DR PRO; PR:Q9NTX7; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; Q9NTX7; protein. DR Bgee; ENSG00000118518; Expressed in cerebellar vermis and 194 other cell types or tissues. DR ExpressionAtlas; Q9NTX7; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0072572; F:poly-ADP-D-ribose binding; IDA:UniProtKB. DR GO; GO:0061630; F:ubiquitin protein ligase activity; TAS:Reactome. DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW. DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; IMP:UniProtKB. DR GO; GO:0051865; P:protein autoubiquitination; IDA:UniProtKB. DR GO; GO:0070936; P:protein K48-linked ubiquitination; IMP:UniProtKB. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IMP:UniProtKB. DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW. DR CDD; cd16546; RING-HC_RNF146; 1. DR FunFam; 3.30.40.10:FF:000204; E3 ubiquitin-protein ligase RNF146; 1. DR FunFam; 3.30.720.50:FF:000003; E3 ubiquitin-protein ligase RNF146; 1. DR Gene3D; 3.30.720.50; -; 1. DR Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 1. DR InterPro; IPR044110; RING-HC_RNF146. DR InterPro; IPR033509; RNF146. DR InterPro; IPR018123; WWE-dom_subgr. DR InterPro; IPR004170; WWE_dom. DR InterPro; IPR037197; WWE_dom_sf. DR InterPro; IPR001841; Znf_RING. DR InterPro; IPR013083; Znf_RING/FYVE/PHD. DR InterPro; IPR017907; Znf_RING_CS. DR PANTHER; PTHR13417; E3 UBIQUITIN-PROTEIN LIGASE RNF146; 1. DR PANTHER; PTHR13417:SF2; E3 UBIQUITIN-PROTEIN LIGASE RNF146; 1. DR Pfam; PF02825; WWE; 1. DR Pfam; PF13920; zf-C3HC4_3; 1. DR SMART; SM00184; RING; 1. DR SMART; SM00678; WWE; 1. DR SUPFAM; SSF57850; RING/U-box; 1. DR SUPFAM; SSF117839; WWE domain; 1. DR PROSITE; PS50918; WWE; 1. DR PROSITE; PS00518; ZF_RING_1; 1. DR PROSITE; PS50089; ZF_RING_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasm; Isopeptide bond; KW Metal-binding; Nucleus; Phosphoprotein; Proteomics identification; KW Reference proteome; Transferase; Ubl conjugation; Ubl conjugation pathway; KW Wnt signaling pathway; Zinc; Zinc-finger. FT CHAIN 1..359 FT /note="E3 ubiquitin-protein ligase RNF146" FT /id="PRO_0000056107" FT DOMAIN 92..168 FT /note="WWE" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00248" FT ZN_FING 37..75 FT /note="RING-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175" FT REGION 254..359 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 284..298 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 306..323 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 108 FT /ligand="a glycoprotein" FT /ligand_id="ChEBI:CHEBI:17089" FT /ligand_part="poly[(1''->2')-ADP-alpha-D-ribose] group" FT /ligand_part_id="ChEBI:CHEBI:157741" FT /evidence="ECO:0000269|PubMed:22267412" FT BINDING 111 FT /ligand="a glycoprotein" FT /ligand_id="ChEBI:CHEBI:17089" FT /ligand_part="poly[(1''->2')-ADP-alpha-D-ribose] group" FT /ligand_part_id="ChEBI:CHEBI:157741" FT /evidence="ECO:0000269|PubMed:22267412" FT BINDING 115 FT /ligand="a glycoprotein" FT /ligand_id="ChEBI:CHEBI:17089" FT /ligand_part="poly[(1''->2')-ADP-alpha-D-ribose] group" FT /ligand_part_id="ChEBI:CHEBI:157741" FT /evidence="ECO:0000269|PubMed:22267412" FT BINDING 145 FT /ligand="a glycoprotein" FT /ligand_id="ChEBI:CHEBI:17089" FT /ligand_part="poly[(1''->2')-ADP-alpha-D-ribose] group" FT /ligand_part_id="ChEBI:CHEBI:157741" FT /evidence="ECO:0000269|PubMed:22267412" FT BINDING 154 FT /ligand="a glycoprotein" FT /ligand_id="ChEBI:CHEBI:17089" FT /ligand_part="poly[(1''->2')-ADP-alpha-D-ribose] group" FT /ligand_part_id="ChEBI:CHEBI:157741" FT /evidence="ECO:0000269|PubMed:22267412" FT BINDING 164 FT /ligand="a glycoprotein" FT /ligand_id="ChEBI:CHEBI:17089" FT /ligand_part="poly[(1''->2')-ADP-alpha-D-ribose] group" FT /ligand_part_id="ChEBI:CHEBI:157741" FT /evidence="ECO:0000269|PubMed:22267412" FT BINDING 176 FT /ligand="a glycoprotein" FT /ligand_id="ChEBI:CHEBI:17089" FT /ligand_part="poly[(1''->2')-ADP-alpha-D-ribose] group" FT /ligand_part_id="ChEBI:CHEBI:157741" FT /evidence="ECO:0000269|PubMed:22267412" FT MOD_RES 290 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q5XIK5" FT MOD_RES 294 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q5XIK5" FT CROSSLNK 85 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:21825151" FT CROSSLNK 95 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:21825151" FT CROSSLNK 131 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:21825151" FT CROSSLNK 176 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:21825151" FT VAR_SEQ 1 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:11230166, FT ECO:0000303|PubMed:14702039, ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:15813938, ECO:0000303|Ref.4" FT /id="VSP_012968" FT VARIANT 25 FT /note="C -> R (in dbSNP:rs10081141)" FT /id="VAR_065249" FT MUTAGEN 54 FT /note="H->A: Partially suppression of WNT3A signaling and FT stabilization of AXIN1, TNKS and TNKS2 with or without FT WNT3A induction. No effect on TNKS1-binding." FT /evidence="ECO:0000269|PubMed:21799911" FT MUTAGEN 106 FT /note="W->A: No effect on Wnt signaling pathway." FT /evidence="ECO:0000269|PubMed:21799911" FT MUTAGEN 108 FT /note="Y->A: Loss of iso-ADP-ribose-binding." FT /evidence="ECO:0000269|PubMed:22267412" FT MUTAGEN 111 FT /note="R->A: Minor effect on iso-ADP-ribose-binding." FT /evidence="ECO:0000269|PubMed:22267412" FT MUTAGEN 115 FT /note="W->A: Strong decrease in iso-ADP-ribose-binding FT affinity." FT /evidence="ECO:0000269|PubMed:22267412" FT MUTAGEN 145 FT /note="Y->A: Loss of iso-ADP-ribose-binding." FT /evidence="ECO:0000269|PubMed:22267412" FT MUTAGEN 154 FT /note="Q->A: Loss of iso-ADP-ribose-binding affinity." FT /evidence="ECO:0000269|PubMed:22267412" FT MUTAGEN 163 FT /note="R->A: Abolishes the ability to recognize and bind FT PARsylated proteins." FT /evidence="ECO:0000269|PubMed:21478859" FT MUTAGEN 164 FT /note="R->A: Loss of iso-ADP-ribose-binding." FT /evidence="ECO:0000269|PubMed:22267412" FT MUTAGEN 176 FT /note="K->A: Minor effect on iso-ADP-ribose-binding." FT /evidence="ECO:0000269|PubMed:22267412" FT CONFLICT 69 FT /note="K -> R (in Ref. 3; BAB55359)" FT /evidence="ECO:0000305" FT CONFLICT 74 FT /note="C -> R (in Ref. 3; BAB55108)" FT /evidence="ECO:0000305" FT CONFLICT 100 FT /note="G -> E (in Ref. 4; CAG38545)" FT /evidence="ECO:0000305" FT CONFLICT 166 FT /note="I -> V (in Ref. 4; CAG38545)" FT /evidence="ECO:0000305" FT CONFLICT 229 FT /note="L -> S (in Ref. 3; BAB55108)" FT /evidence="ECO:0000305" FT CONFLICT 329 FT /note="S -> L (in Ref. 3; BAB55108)" FT /evidence="ECO:0000305" FT STRAND 30..33 FT /evidence="ECO:0007829|PDB:2D8T" FT STRAND 38..43 FT /evidence="ECO:0007829|PDB:2D8T" FT STRAND 45..50 FT /evidence="ECO:0007829|PDB:2D8T" FT TURN 51..53 FT /evidence="ECO:0007829|PDB:2D8T" FT STRAND 54..57 FT /evidence="ECO:0007829|PDB:2D8T" FT HELIX 58..63 FT /evidence="ECO:0007829|PDB:2D8T" FT STRAND 68..70 FT /evidence="ECO:0007829|PDB:2D8T" FT STRAND 72..74 FT /evidence="ECO:0007829|PDB:2D8T" FT HELIX 80..83 FT /evidence="ECO:0007829|PDB:2D8T" FT STRAND 104..109 FT /evidence="ECO:0007829|PDB:3V3L" FT STRAND 111..116 FT /evidence="ECO:0007829|PDB:3V3L" FT HELIX 119..130 FT /evidence="ECO:0007829|PDB:3V3L" FT STRAND 134..140 FT /evidence="ECO:0007829|PDB:3V3L" FT STRAND 143..148 FT /evidence="ECO:0007829|PDB:3V3L" FT TURN 149..152 FT /evidence="ECO:0007829|PDB:3V3L" FT STRAND 153..159 FT /evidence="ECO:0007829|PDB:3V3L" FT STRAND 164..173 FT /evidence="ECO:0007829|PDB:3V3L" SQ SEQUENCE 359 AA; 38950 MW; 7337C410EDA30A7E CRC64; MMAGCGEIDH SINMLPTNRK ANESCSNTAP SLTVPECAIC LQTCVHPVSL PCKHVFCYLC VKGASWLGKR CALCRQEIPE DFLDKPTLLS PEELKAASRG NGEYAWYYEG RNGWWQYDER TSRELEDAFS KGKKNTEMLI AGFLYVADLE NMVQYRRNEH GRRRKIKRDI IDIPKKGVAG LRLDCDANTV NLARESSADG ADSVSAQSGA SVQPLVSSVR PLTSVDGQLT SPATPSPDAS TSLEDSFAHL QLSGDNTAER SHRGEGEEDH ESPSSGRVPA PDTSIEETES DASSDSEDVS AVVAQHSLTQ QRLLVSNANQ TVPDRSDRSG TDRSVAGGGT VSVSVRSRRP DGQCTVTEV // ID SORL_HUMAN Reviewed; 2214 AA. AC Q92673; B2RNX7; Q92856; DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot. DT 18-MAY-2010, sequence version 2. DT 28-JAN-2026, entry version 232. DE RecName: Full=Sortilin-related receptor; DE AltName: Full=Low-density lipoprotein receptor relative with 11 ligand-binding repeats; DE Short=LDLR relative with 11 ligand-binding repeats; DE Short=LR11 {ECO:0000303|PubMed:14764453}; DE AltName: Full=SorLA-1 {ECO:0000303|PubMed:8940146}; DE AltName: Full=Sorting protein-related receptor containing LDLR class A repeats; DE Short=SorLA {ECO:0000303|PubMed:16531402}; DE Flags: Precursor; GN Name=SORL1; Synonyms=C11orf32; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], VARIANTS GLU-1074 AND ILE-1967, AND TISSUE RP SPECIFICITY. RC TISSUE=Brain; RX PubMed=9157966; DOI=10.1161/01.atv.17.5.996; RA Morwald S., Yamazaki H., Bujo H., Kusunoki J., Kanaki T., Seimiya K., RA Morisaki N., Nimpf J., Schneider W.J., Saito Y.; RT "A novel mosaic protein containing LDL receptor elements is highly RT conserved in humans and chickens."; RL Arterioscler. Thromb. Vasc. Biol. 17:996-1002(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 82-91; 114-121; 405-415 AND RP 2019-2030, VARIANTS GLU-1074 AND ILE-1967, TISSUE SPECIFICITY, AND RP INTERACTION WITH LRPAP1. RC TISSUE=Brain; RX PubMed=8940146; DOI=10.1074/jbc.271.49.31379; RA Jacobsen L., Madsen P., Moestrup S.K., Lund A.H., Tommerup N., Nykjaer A., RA Sottrup-Jensen L., Gliemann J., Petersen C.M.; RT "Molecular characterization of a novel human hybrid-type receptor that RT binds the alpha2-macroglobulin receptor-associated protein."; RL J. Biol. Chem. 271:31379-31383(1996). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16554811; DOI=10.1038/nature04632; RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G., RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., RA Hattori M., Rogers J., Lander E.S., Sakaki Y.; RT "Human chromosome 11 DNA sequence and analysis including novel gene RT identification."; RL Nature 440:497-500(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANTS GLU-1074 AND RP ILE-1967. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS GLU-1074 AND ILE-1967. RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP INTERACTION WITH HA, INDUCTION BY HA, SUBCELLULAR LOCATION, AND CLEAVAGE OF RP THE PROPEPTIDE. RX PubMed=11082041; DOI=10.1242/jcs.113.24.4475; RA Hampe W., Riedel I.B., Lintzel J., Bader C.O., Franke I., Schaller H.C.; RT "Ectodomain shedding, translocation and synthesis of SorLA are stimulated RT by its ligand head activator."; RL J. Cell Sci. 113:4475-4485(2000). RN [7] RP PROTEIN SEQUENCE OF 82-86, CLEAVAGE OF THE PROPEPTIDE, INTERACTION WITH HA; RP LRPAP1; NTS AND PROPEPTIDE, SUBCELLULAR LOCATION, GLYCOSYLATION, AND RP MUTAGENESIS OF 78-ARG--ARG-81. RX PubMed=11294867; DOI=10.1074/jbc.m100857200; RA Jacobsen L., Madsen P., Jacobsen C., Nielsen M.S., Gliemann J., RA Petersen C.M.; RT "Activation and functional characterization of the mosaic receptor RT SorLA/LR11."; RL J. Biol. Chem. 276:22788-22796(2001). RN [8] RP INTERACTION WITH HA; LRPAP1 AND PROPEPTIDE. RX PubMed=12530537; DOI=10.1515/bc.2002.193; RA Lintzel J., Franke I., Riedel I.B., Schaller H.C., Hampe W.; RT "Characterization of the VPS10 domain of SorLA/LR11 as binding site for the RT neuropeptide HA."; RL Biol. Chem. 383:1727-1733(2002). RN [9] RP INTERACTION WITH GGA1 AND GGA2. RX PubMed=11821067; DOI=10.1016/s0014-5793(01)03299-9; RA Jacobsen L., Madsen P., Nielsen M.S., Geraerts W.P.M., Gliemann J., RA Smit A.B., Petersen C.M.; RT "The sorLA cytoplasmic domain interacts with GGA1 and -2 and defines RT minimum requirements for GGA binding."; RL FEBS Lett. 511:155-158(2002). RN [10] RP SUBCELLULAR LOCATION, AND INTERACTION WITH LRPAP1; PDGFB; PLAT; PLAU AND RP SERPINE1. RX PubMed=15053742; DOI=10.1042/bj20040149; RA Gliemann J., Hermey G., Nykjaer A., Petersen C.M., Jacobsen C., RA Andreasen P.A.; RT "The mosaic receptor sorLA/LR11 binds components of the plasminogen- RT activating system and platelet-derived growth factor-BB similarly to LRP1 RT (low-density lipoprotein receptor-related protein), but mediates slow RT internalization of bound ligand."; RL Biochem. J. 381:203-212(2004). RN [11] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH PLAUR. RX PubMed=14764453; DOI=10.1161/01.res.0000120862.79154.0f; RA Zhu Y., Bujo H., Yamazaki H., Ohwaki K., Jiang M., Hirayama S., Kanaki T., RA Shibasaki M., Takahashi K., Schneider W.J., Saito Y.; RT "LR11, an LDL receptor gene family member, is a novel regulator of smooth RT muscle cell migration."; RL Circ. Res. 94:752-758(2004). RN [12] RP INTERACTION WITH LRPAP1; GDNF AND PROPEPTIDE. RX PubMed=15364913; DOI=10.1074/jbc.m408873200; RA Westergaard U.B., Soerensen E.S., Hermey G., Nielsen M.S., Nykjaer A., RA Kirkegaard K., Jacobsen C., Gliemann J., Madsen P., Petersen C.M.; RT "Functional organization of the sortilin Vps10p domain."; RL J. Biol. Chem. 279:50221-50229(2004). RN [13] RP FUNCTION IN APP TRAFFICKING, SUBCELLULAR LOCATION, INTERACTION WITH APP, RP AND TISSUE SPECIFICITY. RX PubMed=16174740; DOI=10.1073/pnas.0503689102; RA Andersen O.M., Reiche J., Schmidt V., Gotthardt M., Spoelgen R., Behlke J., RA von Arnim C.A., Breiderhoff T., Jansen P., Wu X., Bales K.R., Cappai R., RA Masters C.L., Gliemann J., Mufson E.J., Hyman B.T., Paul S.M., Nykjaer A., RA Willnow T.E.; RT "Neuronal sorting protein-related receptor sorLA/LR11 regulates processing RT of the amyloid precursor protein."; RL Proc. Natl. Acad. Sci. U.S.A. 102:13461-13466(2005). RN [14] RP INTERACTION WITH PDGFB, SUBCELLULAR LOCATION, AND SHEDDING BY ADAM17. RX PubMed=16393139; DOI=10.1042/bj20051364; RA Hermey G., Sjoegaard S.S., Petersen C.M., Nykjaer A., Gliemann J.; RT "Tumour necrosis factor alpha-converting enzyme mediates ectodomain RT shedding of Vps10p-domain receptor family members."; RL Biochem. J. 395:285-293(2006). RN [15] RP SUBCELLULAR LOCATION, CLEAVAGE BY PSEN1, AND MUTAGENESIS OF RP 2163-ARG-ARG-2164. RX PubMed=16531402; DOI=10.1074/jbc.m601660200; RA Boehm C., Seibel N.M., Henkel B., Steiner H., Haass C., Hampe W.; RT "SorLA signaling by regulated intramembrane proteolysis."; RL J. Biol. Chem. 281:14547-14553(2006). RN [16] RP FUNCTION, AND INTERACTION WITH APP AND BACE1. RX PubMed=16407538; DOI=10.1523/jneurosci.3882-05.2006; RA Spoelgen R., von Arnim C.A., Thomas A.V., Peltan I.D., Koker M., Deng A., RA Irizarry M.C., Andersen O.M., Willnow T.E., Hyman B.T.; RT "Interaction of the cytosolic domains of sorLA/LR11 with the amyloid RT precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme."; RL J. Neurosci. 26:418-428(2006). RN [17] RP INTERACTION WITH APOA5. RX PubMed=17326667; DOI=10.1021/bi7000533; RA Nilsson S.K., Lookene A., Beckstead J.A., Gliemann J., Ryan R.O., RA Olivecrona G.; RT "Apolipoprotein A-V interaction with members of the low density lipoprotein RT receptor gene family."; RL Biochemistry 46:3896-3904(2007). RN [18] RP FUNCTION, INTERACTION WITH APP; GGA1 AND PACS1, SUBCELLULAR LOCATION, AND RP MUTAGENESIS OF 2190-ASP--ASP-2198 AND 2208-ASP--MET-2211. RX PubMed=17855360; DOI=10.1074/jbc.m705073200; RA Schmidt V., Sporbert A., Rohe M., Reimer T., Rehm A., Andersen O.M., RA Willnow T.E.; RT "SorLA/LR11 regulates processing of amyloid precursor protein via RT interaction with adaptors GGA and PACS-1."; RL J. Biol. Chem. 282:32956-32964(2007). RN [19] RP FUNCTION, INTERACTION WITH PACS1; AP-1 COMPLEX AND AP-2 COMPLEX, RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF 2172-PHE--TYR-2177; RP 2190-ASP--ALA-2214; 2190-ASP--ASP-2198; 2201-MET-ILE-2202 AND RP 2211-MET--ALA-2214. RX PubMed=17646382; DOI=10.1128/mcb.00815-07; RA Nielsen M.S., Gustafsen C., Madsen P., Nyengaard J.R., Hermey G., Bakke O., RA Mari M., Schu P., Pohlmann R., Dennes A., Petersen C.M.; RT "Sorting by the cytoplasmic domain of the amyloid precursor protein binding RT receptor SorLA."; RL Mol. Cell. Biol. 27:6842-6851(2007). RN [20] RP FUNCTION, AND INTERACTION WITH APOA5. RX PubMed=18603531; DOI=10.1074/jbc.m802721200; RA Nilsson S.K., Christensen S., Raarup M.K., Ryan R.O., Nielsen M.S., RA Olivecrona G.; RT "Endocytosis of apolipoprotein A-V by members of the low density RT lipoprotein receptor and the VPS10p domain receptor families."; RL J. Biol. Chem. 283:25920-25927(2008). RN [21] RP LACK OF ASSOCIATION WITH SUSCEPTIBILITY TO LATE-ONSET ALZHEIMER DISEASE. RX PubMed=18562096; DOI=10.1016/j.neulet.2008.05.082; RA Minster R.L., DeKosky S.T., Kamboh M.I.; RT "No association of SORL1 SNPs with Alzheimer's disease."; RL Neurosci. Lett. 440:190-192(2008). RN [22] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-99; ASN-1733; ASN-2010; RP ASN-2076 AND ASN-2092. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [23] RP INTERACTION WITH STK39. RX PubMed=20385770; DOI=10.1128/mcb.01560-09; RA Reiche J., Theilig F., Rafiqi F.H., Carlo A.S., Militz D., Mutig K., RA Todiras M., Christensen E.I., Ellison D.H., Bader M., Nykjaer A., RA Bachmann S., Alessi D., Willnow T.E.; RT "SORLA/SORL1 functionally interacts with SPAK to control renal activation RT of Na(+)-K(+)-Cl(-) cotransporter 2."; RL Mol. Cell. Biol. 30:3027-3037(2010). RN [24] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-114, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [25] RP INVOLVEMENT IN AD. RX PubMed=21220680; DOI=10.1001/archneurol.2010.346; RG Genetic and Environmental Risk in Alzheimer Disease 1 Consortium; RA Reitz C., Cheng R., Rogaeva E., Lee J.H., Tokuhiro S., Zou F., Bettens K., RA Sleegers K., Tan E.K., Kimura R., Shibata N., Arai H., Kamboh M.I., RA Prince J.A., Maier W., Riemenschneider M., Owen M., Harold D., RA Hollingworth P., Cellini E., Sorbi S., Nacmias B., Takeda M., RA Pericak-Vance M.A., Haines J.L., Younkin S., Williams J., RA van Broeckhoven C., Farrer L.A., St George-Hyslop P.H., Mayeux R.; RT "Meta-analysis of the association between variants in SORL1 and Alzheimer RT disease."; RL Arch. Neurol. 68:99-106(2011). RN [26] RP PHOSPHORYLATION AT SER-2206, INTERACTION WITH ROCK2, AND TISSUE RP SPECIFICITY. RX PubMed=21147781; DOI=10.1074/jbc.m110.167239; RA Herskowitz J.H., Seyfried N.T., Gearing M., Kahn R.A., Peng J., Levey A.I., RA Lah J.J.; RT "Rho kinase II phosphorylation of the lipoprotein receptor LR11/SORLA RT alters amyloid-beta production."; RL J. Biol. Chem. 286:6117-6127(2011). RN [27] RP FUNCTION, INTERACTION WITH GDNF, AND SUBCELLULAR LOCATION. RX PubMed=21994944; DOI=10.1074/jbc.m111.246413; RA Geng Z., Xu F.Y., Huang S.H., Chen Z.Y.; RT "Sorting protein-related receptor SorLA controls regulated secretion of RT glial cell line-derived neurotrophic factor."; RL J. Biol. Chem. 286:41871-41882(2011). RN [28] RP FUNCTION, INTERACTION WITH LPL, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, RP AND MUTAGENESIS OF 2211-MET--ALA-2214. RX PubMed=21385844; DOI=10.1242/jcs.072538; RA Klinger S.C., Glerup S., Raarup M.K., Mari M.C., Nyegaard M., Koster G., RA Prabakaran T., Nilsson S.K., Kjaergaard M.M., Bakke O., Nykjaer A., RA Olivecrona G., Petersen C.M., Nielsen M.S.; RT "SorLA regulates the activity of lipoprotein lipase by intracellular RT trafficking."; RL J. Cell Sci. 124:1095-1105(2011). RN [29] RP FUNCTION, INTERACTION WITH GDNF; GFRA1; GFRA2; GFRA3 AND GFRA4, AND RP SUBCELLULAR LOCATION. RX PubMed=23333276; DOI=10.1016/j.celrep.2012.12.011; RA Glerup S., Lume M., Olsen D., Nyengaard J.R., Vaegter C.B., Gustafsen C., RA Christensen E.I., Kjolby M., Hay-Schmidt A., Bender D., Madsen P., RA Saarma M., Nykjaer A., Petersen C.M.; RT "SorLA controls neurotrophic activity by sorting of GDNF and its receptors RT GFRalpha1 and RET."; RL Cell Rep. 3:186-199(2013). RN [30] RP FUNCTION, INTERACTION WITH PLAUR, AND INDUCTION BY HYPOXIA. RX PubMed=23486467; DOI=10.1074/jbc.m112.442491; RA Nishii K., Nakaseko C., Jiang M., Shimizu N., Takeuchi M., Schneider W.J., RA Bujo H.; RT "The soluble form of LR11 protein is a regulator of hypoxia-induced, RT urokinase-type plasminogen activator receptor (uPAR)-mediated adhesion of RT immature hematological cells."; RL J. Biol. Chem. 288:11877-11886(2013). RN [31] RP INVOLVEMENT IN AD. RX PubMed=23565137; DOI=10.1371/journal.pone.0058618; RG Alzheimer Disease Genetics Consortium; RA Miyashita A., Koike A., Jun G., Wang L.S., Takahashi S., Matsubara E., RA Kawarabayashi T., Shoji M., Tomita N., Arai H., Asada T., Harigaya Y., RA Ikeda M., Amari M., Hanyu H., Higuchi S., Ikeuchi T., Nishizawa M., RA Suga M., Kawase Y., Akatsu H., Kosaka K., Yamamoto T., Imagawa M., RA Hamaguchi T., Yamada M., Moriaha T., Takeda M., Takao T., Nakata K., RA Fujisawa Y., Sasaki K., Watanabe K., Nakashima K., Urakami K., Ooya T., RA Takahashi M., Yuzuriha T., Serikawa K., Yoshimoto S., Nakagawa R., RA Kim J.W., Ki C.S., Won H.H., Na D.L., Seo S.W., Mook-Jung I., RA St George-Hyslop P., Mayeux R., Haines J.L., Pericak-Vance M.A., RA Yoshida M., Nishida N., Tokunaga K., Yamamoto K., Tsuji S., Kanazawa I., RA Ihara Y., Schellenberg G.D., Farrer L.A., Kuwano R.; RT "SORL1 is genetically associated with late-onset Alzheimer's disease in RT Japanese, Koreans and Caucasians."; RL PLoS ONE 8:E58618-E58618(2013). RN [32] RP FUNCTION. RX PubMed=23977241; DOI=10.1371/journal.pone.0072164; RA Rohe M., Hartl D., Fjorback A.N., Klose J., Willnow T.E.; RT "SORLA-mediated trafficking of TrkB enhances the response of neurons to RT BDNF."; RL PLoS ONE 8:E72164-E72164(2013). RN [33] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [34] RP FUNCTION, INTERACTION WITH APP AND PROPEPTIDE, AND CHARACTERIZATION OF RP VARIANT AD ARG-511. RX PubMed=24523320; DOI=10.1126/scitranslmed.3007747; RA Caglayan S., Takagi-Niidome S., Liao F., Carlo A.S., Schmidt V., RA Burgert T., Kitago Y., Fuechtbauer E.M., Fuechtbauer A., Holtzman D.M., RA Takagi J., Willnow T.E.; RT "Lysosomal sorting of amyloid-beta by the SORLA receptor is impaired by a RT familial Alzheimer's disease mutation."; RL Sci. Transl. Med. 6:223RA20-223RA20(2014). RN [35] RP POTENTIAL ASSOCIATION WITH BODY MASS INDEX. RX PubMed=26584636; DOI=10.1038/ncomms9951; RA Whittle A.J., Jiang M., Peirce V., Relat J., Virtue S., Ebinuma H., RA Fukamachi I., Yamaguchi T., Takahashi M., Murano T., Tatsuno I., RA Takeuchi M., Nakaseko C., Jin W., Jin Z., Campbell M., Schneider W.J., RA Vidal-Puig A., Bujo H.; RT "Soluble LR11/SorLA represses thermogenesis in adipose tissue and RT correlates with BMI in humans."; RL Nat. Commun. 6:8951-8951(2015). RN [36] RP FUNCTION, INTERACTION WITH INSR, AND POTENTIAL ASSOCIATION WITH BODY MASS RP INDEX. RX PubMed=27322061; DOI=10.1172/jci84708; RA Schmidt V., Schulz N., Yan X., Schuermann A., Kempa S., Kern M., RA Blueher M., Poy M.N., Olivecrona G., Willnow T.E.; RT "SORLA facilitates insulin receptor signaling in adipocytes and exacerbates RT obesity."; RL J. Clin. Invest. 126:2706-2720(2016). RN [37] RP FUNCTION, AND INTERACTION WITH CLCF1; CRLF1; CNTFR AND LRPAP1. RX PubMed=26858303; DOI=10.1128/mcb.00917-15; RA Larsen J.V., Kristensen A.M., Pallesen L.T., Bauer J., Vaegter C.B., RA Nielsen M.S., Madsen P., Petersen C.M.; RT "Cytokine-like factor 1, an essential facilitator of cardiotrophin-like RT cytokine:ciliary neurotrophic factor receptor alpha signaling and sorLA- RT mediated turnover."; RL Mol. Cell. Biol. 36:1272-1286(2016). RN [38] RP FUNCTION, INTERACTION WITH IL6 AND IL6R, AND SHEDDING FROM THE CELL RP SURFACE. RX PubMed=28265003; DOI=10.1128/mcb.00641-16; RA Larsen J.V., Petersen C.M.; RT "SorLA in Interleukin-6 Signaling and Turnover."; RL Mol. Cell. Biol. 37:0-0(2017). RN [39] RP INTERACTION WITH APOE. RX PubMed=30448281; DOI=10.1016/j.cca.2018.11.024; RA Yano K., Hirayama S., Misawa N., Furuta A., Ueno T., Motoi Y., Seino U., RA Ebinuma H., Ikeuchi T., Schneider W.J., Bujo H., Miida T.; RT "Soluble LR11 competes with amyloid beta in binding to cerebrospinal fluid- RT high-density lipoprotein."; RL Clin. Chim. Acta 489:29-34(2019). RN [40] RP FUNCTION, INTERACTION WITH ERBB2, AND SUBCELLULAR LOCATION. RX PubMed=31138794; DOI=10.1038/s41467-019-10275-0; RA Pietilae M., Sahgal P., Peuhu E., Jaentti N.Z., Paatero I., Naervae E., RA Al-Akhrass H., Lilja J., Georgiadou M., Andersen O.M., Padzik A., Sihto H., RA Joensuu H., Blomqvist M., Saarinen I., Bostroem P.J., Taimen P., Ivaska J.; RT "SORLA regulates endosomal trafficking and oncogenic fitness of HER2."; RL Nat. Commun. 10:2340-2340(2019). RN [41] RP INTERACTION WITH GGA1 AND HSPA12A, AND MUTAGENESIS OF 2190-ASP-ASP-2191; RP 2194-GLU--ASP-2198; 2203-THR-GLY-2204; 2205-PHE-SER-2206; 2207-ASP-ASP-2208 RP AND 2209-VAL-PRO-2210. RX PubMed=30679749; DOI=10.1038/s41598-018-37336-6; RA Madsen P., Isaksen T.J., Siupka P., Toth A.E., Nyegaard M., Gustafsen C., RA Nielsen M.S.; RT "HSPA12A targets the cytoplasmic domain and affects the trafficking of the RT Amyloid Precursor Protein receptor SorLA."; RL Sci. Rep. 9:611-611(2019). RN [42] RP STRUCTURE BY NMR OF 1651-1745. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of the second FN3 domain of human SORLA/LR11."; RL Submitted (OCT-2006) to the PDB data bank. RN [43] RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 2202-2214 IN COMPLEX WITH GGA1, RP AND INTERACTION WITH GGA1. RX PubMed=20015111; DOI=10.1111/j.1600-0854.2009.01017.x; RA Cramer J.F., Gustafsen C., Behrens M.A., Oliveira C.L., Pedersen J.S., RA Madsen P., Petersen C.M., Thirup S.S.; RT "GGA autoinhibition revisited."; RL Traffic 11:259-273(2010). RN [44] RP VARIANTS [LARGE SCALE ANALYSIS] SER-120; LEU-1581 AND VAL-1972. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). RN [45] RP POSSIBLE ASSOCIATION WITH SUSCEPTIBILITY TO LATE-ONSET ALZHEIMER DISEASE, RP AND VARIANT THR-528. RX PubMed=18407551; DOI=10.1002/humu.20725; RA Bettens K., Brouwers N., Engelborghs S., De Deyn P.P., Van Broeckhoven C., RA Sleegers K.; RT "SORL1 is genetically associated with increased risk for late-onset RT Alzheimer disease in the Belgian population."; RL Hum. Mutat. 29:769-770(2008). RN [46] RP VARIANTS AD CYS-141; ARG-511; SER-924; SER-1358 AND ASP-1681. RX PubMed=22472873; DOI=10.1038/mp.2012.15; RG PHRC GMAJ Collaborators; RA Pottier C., Hannequin D., Coutant S., Rovelet-Lecrux A., Wallon D., RA Rousseau S., Legallic S., Paquet C., Bombois S., Pariente J., RA Thomas-Anterion C., Michon A., Croisile B., Etcharry-Bouyx F., Berr C., RA Dartigues J.F., Amouyel P., Dauchel H., Boutoleau-Bretonniere C., RA Thauvin C., Frebourg T., Lambert J.C., Campion D.; RT "High frequency of potentially pathogenic SORL1 mutations in autosomal RT dominant early-onset Alzheimer disease."; RL Mol. Psychiatry 17:875-879(2012). CC -!- FUNCTION: Sorting receptor that directs several proteins to their CC correct location within the cell (Probable). Along with AP-1 complex, CC involved Golgi apparatus - endosome sorting (PubMed:17646382). Sorting CC receptor for APP, regulating its intracellular trafficking and CC processing into amyloidogenic-beta peptides. Retains APP in the trans- CC Golgi network, hence preventing its transit through late endosomes CC where amyloid beta peptides Abeta40 and Abeta42 are generated CC (PubMed:16174740, PubMed:16407538, PubMed:17855360, PubMed:24523320). CC May also sort newly produced amyloid-beta peptides to lysosomes for CC catabolism (PubMed:24523320). Does not affect APP trafficking from the CC endoplasmic reticulum to Golgi compartments (PubMed:17855360). Sorting CC receptor for the BDNF receptor NTRK2/TRKB that facilitates NTRK2 CC trafficking between synaptic plasma membranes, postsynaptic densities CC and cell soma, hence positively regulates BDNF signaling by controlling CC the intracellular location of its receptor (PubMed:23977241). Sorting CC receptor for GDNF that promotes GDNF regulated, but not constitutive CC secretion (PubMed:21994944). Sorting receptor for the GDNF-GFRA1 CC complex, directing it from the cell surface to endosomes. GDNF is then CC targeted to lysosomes and degraded, while its receptor GFRA1 recycles CC back to the cell membrane, resulting in a GDNF clearance pathway. The CC SORL1-GFRA1 complex further targets RET for endocytosis, but not for CC degradation, affecting GDNF-induced neurotrophic activities CC (PubMed:23333276). Sorting receptor for ERBB2/HER2. Regulates ERBB2 CC subcellular distribution by promoting its recycling after CC internalization from endosomes back to the plasma membrane, hence CC stimulating phosphoinositide 3-kinase (PI3K)-dependent ERBB2 signaling. CC In ERBB2-dependent cancer cells, promotes cell proliferation CC (PubMed:31138794). Sorting receptor for lipoprotein lipase LPL. CC Promotes LPL localization to endosomes and later to the lysosomes, CC leading to degradation of newly synthesized LPL (PubMed:21385844). CC Potential sorting receptor for APOA5, inducing APOA5 internalization to CC early endosomes, then to late endosomes, wherefrom a portion is sent to CC lysosomes and degradation, another portion is sorted to the trans-Golgi CC network (PubMed:18603531). Sorting receptor for the insulin receptor CC INSR. Promotes recycling of internalized INSR via the Golgi apparatus CC back to the cell surface, thereby preventing lysosomal INSR catabolism, CC increasing INSR cell surface expression and strengthening insulin CC signal reception in adipose tissue. Does not affect INSR CC internalization (PubMed:27322061). Plays a role in renal ion CC homeostasis, controlling the phospho-regulation of SLC12A1/NKCC2 by CC STK39/SPAK kinase and PPP3CB/calcineurin A beta phosphatase, possibly CC through intracellular sorting of STK39 and PPP3CB (By similarity). CC Stimulates, via the N-terminal ectodomain, the proliferation and CC migration of smooth muscle cells, possibly by increasing cell surface CC expression of the urokinase receptor uPAR/PLAUR. This may promote CC extracellular matrix proteolysis and hence facilitate cell migration CC (PubMed:14764453). By acting on the migration of intimal smooth muscle CC cells, may accelerate intimal thickening following vascular injury CC (PubMed:14764453). Promotes adhesion of monocytes (PubMed:23486467). CC Stimulates proliferation and migration of monocytes/macrophages (By CC similarity). Through its action on intimal smooth muscle cells and CC macrophages, may accelerate intimal thickening and macrophage foam cell CC formation in the process of atherosclerosis (By similarity). Regulates CC hypoxia-enhanced adhesion of hematopoietic stem and progenitor cells to CC the bone marrow stromal cells via a PLAUR-mediated pathway. This CC function is mediated by the N-terminal ectodomain (PubMed:23486467). CC Metabolic regulator, which functions to maintain the adequate balance CC between lipid storage and oxidation in response to changing CC environmental conditions, such as temperature and diet. The N-terminal CC ectodomain negatively regulates adipose tissue energy expenditure, CC acting through the inhibition the BMP/Smad pathway (By similarity). May CC regulate signaling by the heterodimeric neurotrophic cytokine CLCF1- CC CRLF1 bound to the CNTFR receptor by promoting the endocytosis of the CC tripartite complex CLCF1-CRLF1-CNTFR and lysosomal degradation CC (PubMed:26858303). May regulate IL6 signaling, decreasing cis CC signaling, possibly by interfering with IL6-binding to membrane-bound CC IL6R, while up-regulating trans signaling via soluble IL6R CC (PubMed:28265003). {ECO:0000250|UniProtKB:O88307, CC ECO:0000269|PubMed:14764453, ECO:0000269|PubMed:16174740, CC ECO:0000269|PubMed:16407538, ECO:0000269|PubMed:17646382, CC ECO:0000269|PubMed:17855360, ECO:0000269|PubMed:18603531, CC ECO:0000269|PubMed:21385844, ECO:0000269|PubMed:21994944, CC ECO:0000269|PubMed:23333276, ECO:0000269|PubMed:23486467, CC ECO:0000269|PubMed:23977241, ECO:0000269|PubMed:24523320, CC ECO:0000269|PubMed:26858303, ECO:0000269|PubMed:27322061, CC ECO:0000269|PubMed:28265003, ECO:0000269|PubMed:31138794, ECO:0000305}. CC -!- SUBUNIT: After maturation cleavage, interacts (via N-terminus) with its CC own propeptide; this interaction prevents interaction with other CC ligands, including CRLF1, GDNF, GFRA1, IL6 and IL6R (PubMed:11294867, CC PubMed:12530537, PubMed:15364913, PubMed:23333276, PubMed:24523320). CC Interacts (via N-terminal ectodomain) with APP, forming a 1:1 CC stoichiometric complex, including with isoforms APP695, APP751 and CC APP770; this interaction retains APP in the trans-Golgi network and CC reduces processing into soluble APP-alpha and amyloid-beta peptides CC (PubMed:16174740, PubMed:16407538, PubMed:17855360, PubMed:24523320). CC Also interacts with APP C-terminal fragment C99 and with Abeta40 CC (PubMed:16407538). Interacts with beta-secretase BACE1/BACE; this CC interaction may affect BACE1-binding to APP and hence reduce BACE1- CC dependent APP cleavage (PubMed:16407538). Interacts with LRPAP1/RAP CC (PubMed:11294867, PubMed:12530537, PubMed:14764453, PubMed:15053742, CC PubMed:15364913, PubMed:26858303, PubMed:8940146). Interacts (via C- CC terminal cytosolic domain) with GGA1 and GGA2 (via N-terminal VHS CC domain) (PubMed:11821067, PubMed:17855360, PubMed:20015111, CC PubMed:30679749). Interacts with PACS1 (PubMed:17646382, CC PubMed:17855360). May interact (via the N-terminal ectodomain) with the CC morphogenetic neuropeptide, also called head activator or HA; this CC interaction is impaired in the presence of propeptide (PubMed:11082041, CC PubMed:11294867, PubMed:12530537). Interacts with neurotensin/NTS CC (PubMed:11294867). Interacts (via the N-terminal ectodomain) with PDGFB CC homodimer (PubMed:15053742, PubMed:16393139). Interacts (via N-terminal CC ectodomain) with the uPA receptor PLAUR; this interaction decreases CC PLAUR internalization (PubMed:14764453, PubMed:23486467). Interacts CC (via N-terminal ectodomain) with uPA/PLAU and PAI1/SERPINE1, either CC individually or in complex with each other, leading to endocytosis; CC this interaction is abolished in the presence of LRPAP1 CC (PubMed:15053742). Also interacts with the ternary complex composed of CC PLAUR-PLAU-PAI1 (PubMed:15053742). Also interacts with tPA/PLAT either CC alone or in complex with SERPINE1 (PubMed:15053742). Interacts (via C- CC terminus) with AP-1 and AP-2 complexes (PubMed:17646382). Interacts CC with BMPR1A and BMPR1B (By similarity). Interacts with lipoprotein CC lipase LPL; this interaction is optimal in slightly acidic conditions CC (PubMed:21385844). Interacts (via N-terminal ectodomain) with GDNF (via CC propeptide) and GDNF receptor alpha-1/GFRA1, either individually or in CC complex with each other (PubMed:15364913, PubMed:21994944, CC PubMed:23333276). The interaction with GDNF occurs mostly CC intracellularly (PubMed:21994944). Also interacts with other GDNF CC receptor alpha family members, including GFRA2, GFRA3 and GFRA4 CC (PubMed:23333276). Interacts with the insulin receptor INSR; this CC interaction strongly increases the surface exposure of INSR CC (PubMed:27322061). Interacts (via cytosolic C-terminus) with STK39/SPAK CC (PubMed:20385770). Interacts (via N-terminal ectodomain) with the CC heterodimeric complex CRLF1-CLC; within this complex, the interaction CC is mediated predominantly by the CRLF1 moiety (PubMed:26858303). CC Interacts with CNTFR, as well as with the tripartite signaling complex CC formed by CRLF1, CLC and CNTFR (PubMed:26858303). Interacts (via N- CC terminal ectodomain) with IL6; this interaction leads to IL6 CC internalization and lysosomal degradation (PubMed:28265003). Binding of CC SOLRL1 secreted N-terminal ectodomain to IL6 may increase IL6 trans CC signaling (PubMed:28265003). Interacts with secreted IL6R; this CC interaction leads to IL6R internalization (PubMed:28265003). Also CC interacts with transmembrane IL6R; this interaction does not affect CC IL6R subcellular location (PubMed:28265003). Interacts with APOE CC (PubMed:30448281). Interacts with apolipoprotein E-rich beta-VLDL (By CC similarity). Interacts with APOA5; this interaction leads to APOA5 CC internalization and is abolished by heparin (PubMed:17326667, CC PubMed:18603531). Interaction with APOA5 results in enhanced binding to CC chylomicrons (PubMed:17326667). Interacts with ROCK2 (PubMed:21147781). CC Interacts (via cytosolic C-terminus) with PPP3CB/calcineurin A beta (By CC similarity). Interacts with NTRK2/TRKB; this interaction facilitates CC NTRK2 trafficking between synaptic plasma membranes, postsynaptic CC densities and cell soma, hence positively regulates BDNF signaling (By CC similarity). Interacts (via cytosolic C-terminus) with HSPA12A in an CC ADP-dependent manner; this interaction affects SORL1 internalization CC and subcellular localization (PubMed:30679749). Interacts (via N- CC terminal ectodomain) with ERBB2/HER2 (PubMed:31138794). CC {ECO:0000250|UniProtKB:O88307, ECO:0000250|UniProtKB:Q95209, CC ECO:0000269|PubMed:11082041, ECO:0000269|PubMed:11294867, CC ECO:0000269|PubMed:11821067, ECO:0000269|PubMed:12530537, CC ECO:0000269|PubMed:14764453, ECO:0000269|PubMed:15053742, CC ECO:0000269|PubMed:15364913, ECO:0000269|PubMed:16174740, CC ECO:0000269|PubMed:16393139, ECO:0000269|PubMed:16407538, CC ECO:0000269|PubMed:17326667, ECO:0000269|PubMed:17646382, CC ECO:0000269|PubMed:17855360, ECO:0000269|PubMed:18603531, CC ECO:0000269|PubMed:20015111, ECO:0000269|PubMed:20385770, CC ECO:0000269|PubMed:21147781, ECO:0000269|PubMed:21385844, CC ECO:0000269|PubMed:21994944, ECO:0000269|PubMed:23333276, CC ECO:0000269|PubMed:23486467, ECO:0000269|PubMed:24523320, CC ECO:0000269|PubMed:26858303, ECO:0000269|PubMed:27322061, CC ECO:0000269|PubMed:28265003, ECO:0000269|PubMed:30448281, CC ECO:0000269|PubMed:30679749, ECO:0000269|PubMed:31138794, CC ECO:0000269|PubMed:8940146}. CC -!- INTERACTION: CC Q92673; P05067: APP; NbExp=5; IntAct=EBI-1171329, EBI-77613; CC Q92673; P05067-4: APP; NbExp=8; IntAct=EBI-1171329, EBI-302641; CC Q92673; PRO_0000000091 [P05067]: APP; NbExp=4; IntAct=EBI-1171329, EBI-3894543; CC Q92673; PRO_0000000093 [P05067]: APP; NbExp=3; IntAct=EBI-1171329, EBI-2431589; CC Q92673; P83916: CBX1; NbExp=3; IntAct=EBI-1171329, EBI-78129; CC Q92673; P43681: CHRNA4; NbExp=3; IntAct=EBI-1171329, EBI-7132379; CC Q92673; P26992: CNTFR; NbExp=7; IntAct=EBI-1171329, EBI-743758; CC Q92673; O75462: CRLF1; NbExp=3; IntAct=EBI-1171329, EBI-15587902; CC Q92673; Q96D03: DDIT4L; NbExp=3; IntAct=EBI-1171329, EBI-742054; CC Q92673; P20042: EIF2S2; NbExp=3; IntAct=EBI-1171329, EBI-711977; CC Q92673; PRO_0000034005 [P39905]: GDNF; NbExp=6; IntAct=EBI-1171329, EBI-25397146; CC Q92673; P56159-2: GFRA1; NbExp=3; IntAct=EBI-1171329, EBI-15854635; CC Q92673; Q9UJY5: GGA1; NbExp=5; IntAct=EBI-1171329, EBI-447141; CC Q92673; Q9UJY4: GGA2; NbExp=6; IntAct=EBI-1171329, EBI-447646; CC Q92673; O43301: HSPA12A; NbExp=5; IntAct=EBI-1171329, EBI-296980; CC Q92673; P05231: IL6; NbExp=4; IntAct=EBI-1171329, EBI-720533; CC Q92673; P08887: IL6R; NbExp=7; IntAct=EBI-1171329, EBI-299383; CC Q92673; Q92993: KAT5; NbExp=3; IntAct=EBI-1171329, EBI-399080; CC Q92673; P30533: LRPAP1; NbExp=5; IntAct=EBI-1171329, EBI-715927; CC Q92673; P19404: NDUFV2; NbExp=3; IntAct=EBI-1171329, EBI-713665; CC Q92673; P00491: PNP; NbExp=3; IntAct=EBI-1171329, EBI-712238; CC Q92673; P78424: POU6F2; NbExp=3; IntAct=EBI-1171329, EBI-12029004; CC Q92673; Q15669: RHOH; NbExp=3; IntAct=EBI-1171329, EBI-1244971; CC Q92673; PRO_0000033164 [Q92673]: SORL1; NbExp=9; IntAct=EBI-1171329, EBI-25298876; CC Q92673; Q8N0S8: VPS29; NbExp=3; IntAct=EBI-1171329, EBI-25892084; CC Q92673; Q62997: Gfra1; Xeno; NbExp=5; IntAct=EBI-1171329, EBI-25397991; CC -!- SUBCELLULAR LOCATION: Golgi apparatus membrane CC {ECO:0000269|PubMed:11294867, ECO:0000269|PubMed:16174740, CC ECO:0000269|PubMed:17855360, ECO:0000269|PubMed:21385844, CC ECO:0000269|PubMed:21994944}; Single-pass type I membrane protein CC {ECO:0000305}. Golgi apparatus, trans-Golgi network membrane CC {ECO:0000269|PubMed:17646382, ECO:0000269|PubMed:21385844, CC ECO:0000269|PubMed:23333276}; Single-pass type I membrane protein CC {ECO:0000305}. Endosome membrane {ECO:0000269|PubMed:21385844, CC ECO:0000269|PubMed:23333276}; Single-pass type I membrane protein CC {ECO:0000305}. Early endosome membrane {ECO:0000269|PubMed:16174740, CC ECO:0000269|PubMed:17646382, ECO:0000269|PubMed:21385844, CC ECO:0000269|PubMed:31138794}; Single-pass type I membrane protein CC {ECO:0000305}. Recycling endosome membrane CC {ECO:0000269|PubMed:17855360, ECO:0000269|PubMed:31138794}; Single-pass CC type I membrane protein {ECO:0000305}. Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:17855360, ECO:0000269|PubMed:21385844}; Single-pass CC type I membrane protein {ECO:0000305}. Endosome, multivesicular body CC membrane {ECO:0000269|PubMed:21385844, ECO:0000269|PubMed:23333276}; CC Single-pass type I membrane protein {ECO:0000305}. Cell membrane CC {ECO:0000269|PubMed:11294867, ECO:0000269|PubMed:14764453, CC ECO:0000269|PubMed:15053742, ECO:0000269|PubMed:17855360, CC ECO:0000269|PubMed:21385844, ECO:0000269|PubMed:21994944, CC ECO:0000269|PubMed:31138794}; Single-pass type I membrane protein CC {ECO:0000305}. Cytoplasmic vesicle, secretory vesicle membrane CC {ECO:0000269|PubMed:21994944}; Single-pass type I membrane protein CC {ECO:0000305}. Secreted {ECO:0000269|PubMed:11082041, CC ECO:0000269|PubMed:14764453, ECO:0000269|PubMed:15053742, CC ECO:0000269|PubMed:16393139, ECO:0000269|PubMed:16531402}. Note=Mostly CC intracellular, predominantly in the trans-Golgi network (TGN) and in CC endosome, as well as in endosome-to-TGN retrograde vesicles; found at CC low levels on the plasma membrane (PubMed:11294867, PubMed:15053742, CC PubMed:17855360, PubMed:21385844, PubMed:21994944, PubMed:31138794). At CC the cell surface, partially subjected to proteolytic shedding that CC releases the ectodomain (also called soluble SORLA, solLR11 or sLR11) CC in the extracellular milieu (PubMed:11082041, PubMed:16393139, CC PubMed:16531402). The shedding may be catalyzed by ADAM17/TACE CC (PubMed:16393139). Following shedding, PSEN1/presenilin-1 cleaves the CC remaining transmembrane fragment and catalyzes the release of a C- CC terminal fragment in the cytosol and of a soluble N-terminal beta CC fragment in the extracellular milieu. The C-terminal cytosolic fragment CC localizes to the nucleus (PubMed:16531402). At the cell surface, the CC full-length protein undergoes partial clathrin-dependent endocytosis CC guided by clathrin adapter protein 2 (AP-2) (PubMed:11294867, CC PubMed:15053742, PubMed:17646382). {ECO:0000269|PubMed:11082041, CC ECO:0000269|PubMed:11294867, ECO:0000269|PubMed:15053742, CC ECO:0000269|PubMed:16393139, ECO:0000269|PubMed:16531402, CC ECO:0000269|PubMed:17646382, ECO:0000269|PubMed:17855360, CC ECO:0000269|PubMed:21385844, ECO:0000269|PubMed:21994944, CC ECO:0000269|PubMed:31138794}. CC -!- TISSUE SPECIFICITY: Highly expressed in brain (at protein level) CC (PubMed:16174740, PubMed:21147781, PubMed:9157966). Most abundant in CC the cerebellum, cerebral cortex and occipital pole; low levels in the CC putamen and thalamus (PubMed:16174740, PubMed:9157966). Expression is CC significantly reduced in the frontal cortex of patients suffering from CC Alzheimer disease (PubMed:16174740). Also expressed in spinal cord, CC spleen, testis, prostate, ovary, thyroid and lymph nodes CC (PubMed:8940146, PubMed:9157966). {ECO:0000269|PubMed:16174740, CC ECO:0000269|PubMed:21147781, ECO:0000269|PubMed:8940146, CC ECO:0000269|PubMed:9157966}. CC -!- INDUCTION: Up-regulated by morphogenetic neuropeptide, also called head CC activator or HA (PubMed:11082041). Up-regulated under hypoxic CC conditions in hematopoietic stem and progenitor cells, a physiological CC condition encountered by these cells in the endosteum. This up- CC regulation may be mediated by HIF1A-induced transcription CC (PubMed:23486467). {ECO:0000269|PubMed:11082041, CC ECO:0000269|PubMed:23486467}. CC -!- PTM: Within the Golgi apparatus, the propeptide may be cleaved off by CC FURIN or a furin-like protease (Probable). After cleavage, the CC propeptide interacts with the mature protein N-terminus, preventing the CC association with other ligands (PubMed:11294867). At the cell surface, CC partially subjected to proteolytic shedding that releases the CC ectodomain in the extracellular milieu (PubMed:11082041, CC PubMed:16393139, PubMed:16531402, PubMed:28265003). The shedding may be CC catalyzed by ADAM17/TACE (PubMed:16393139, PubMed:16531402). Following CC shedding, PSEN1/presenilin-1 cleaves the remaining transmembrane CC fragment and catalyzes the release of a C-terminal fragment in the CC cytosol and of a soluble N-terminal beta fragment in the extracellular CC milieu. The C-terminal cytosolic fragment localizes to the nucleus CC (PubMed:16531402). {ECO:0000269|PubMed:11082041, CC ECO:0000269|PubMed:11294867, ECO:0000269|PubMed:16393139, CC ECO:0000269|PubMed:16531402, ECO:0000269|PubMed:28265003, CC ECO:0000305|PubMed:11082041, ECO:0000305|PubMed:11294867}. CC -!- PTM: Phosphorylation at Ser-2206 facilitates the interaction with GGA1. CC {ECO:0000269|PubMed:20015111}. CC -!- DISEASE: Alzheimer disease (AD) [MIM:104300]: Alzheimer disease is a CC neurodegenerative disorder characterized by progressive dementia, loss CC of cognitive abilities, and deposition of fibrillar amyloid proteins as CC intraneuronal neurofibrillary tangles, extracellular amyloid plaques CC and vascular amyloid deposits. The major constituents of these plaques CC are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, CC that are produced by the proteolysis of the transmembrane APP protein. CC The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved CC products, such as C31, are also implicated in neuronal death. CC {ECO:0000269|PubMed:21220680, ECO:0000269|PubMed:22472873, CC ECO:0000269|PubMed:23565137, ECO:0000269|PubMed:24523320}. Note=The CC gene represented in this entry may be involved in disease pathogenesis. CC -!- MISCELLANEOUS: There may be a positive correlation of body mass index CC with levels of SORL1 transcript and SORLA protein in visceral adipose CC tissue. {ECO:0000269|PubMed:27322061}. CC -!- SIMILARITY: Belongs to the VPS10-related sortilin family. SORL1 CC subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; Y08110; CAA69325.1; -; mRNA. DR EMBL; U60975; AAC50891.2; -; mRNA. DR EMBL; AP000664; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP000977; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471065; EAW67525.1; -; Genomic_DNA. DR EMBL; BC137171; AAI37172.1; -; mRNA. DR CCDS; CCDS8436.1; -. DR RefSeq; NP_003096.2; NM_003105.6. DR PDB; 2DM4; NMR; -; A=1651-1745. DR PDB; 3G2S; X-ray; 1.70 A; C/D=2202-2214. DR PDB; 3G2T; X-ray; 2.00 A; C/D=2202-2214. DR PDB; 3WSX; X-ray; 2.35 A; A=29-753. DR PDB; 3WSY; X-ray; 3.11 A; A=86-753, C=42-56. DR PDB; 3WSZ; X-ray; 3.20 A; A=86-753. DR PDB; 7VT0; EM; 3.40 A; A/B=89-752. DR PDBsum; 2DM4; -. DR PDBsum; 3G2S; -. DR PDBsum; 3G2T; -. DR PDBsum; 3WSX; -. DR PDBsum; 3WSY; -. DR PDBsum; 3WSZ; -. DR PDBsum; 7VT0; -. DR AlphaFoldDB; Q92673; -. DR BMRB; Q92673; -. DR EMDB; EMD-32117; -. DR SMR; Q92673; -. DR BioGRID; 112536; 163. DR CORUM; Q92673; -. DR DIP; DIP-41229N; -. DR FunCoup; Q92673; 1351. DR IntAct; Q92673; 141. DR MINT; Q92673; -. DR STRING; 9606.ENSP00000260197; -. DR TCDB; 9.B.87.1.17; the selenoprotein p receptor (selp-receptor) family. DR GlyConnect; 1766; 17 N-Linked glycans (11 sites). DR GlyCosmos; Q92673; 35 sites, 18 glycans. DR GlyGen; Q92673; 45 sites, 94 N-linked glycans (19 sites), 5 O-linked glycans (10 sites). DR iPTMnet; Q92673; -. DR PhosphoSitePlus; Q92673; -. DR SwissPalm; Q92673; -. DR BioMuta; SORL1; -. DR DMDM; 296452912; -. DR jPOST; Q92673; -. DR MassIVE; Q92673; -. DR PaxDb; 9606-ENSP00000260197; -. DR PeptideAtlas; Q92673; -. DR ProteomicsDB; 75402; -. DR Pumba; Q92673; -. DR ABCD; Q92673; 1 sequenced antibody. DR Antibodypedia; 32786; 274 antibodies from 39 providers. DR DNASU; 6653; -. DR Ensembl; ENST00000260197.12; ENSP00000260197.6; ENSG00000137642.14. DR GeneID; 6653; -. DR KEGG; hsa:6653; -. DR MANE-Select; ENST00000260197.12; ENSP00000260197.6; NM_003105.6; NP_003096.2. DR UCSC; uc001pxx.4; human. DR AGR; HGNC:11185; -. DR ClinPGx; PA36022; -. DR CTD; 6653; -. DR DisGeNET; 6653; -. DR GeneCards; SORL1; -. DR HGNC; HGNC:11185; SORL1. DR HPA; ENSG00000137642; Low tissue specificity. DR MalaCards; SORL1; -. DR MIM; 104300; phenotype. DR MIM; 602005; gene. DR NIAGADS; ENSG00000137642; -. DR OpenTargets; ENSG00000137642; -. DR Orphanet; 1020; Early-onset autosomal dominant Alzheimer disease. DR VEuPathDB; HostDB:ENSG00000137642; -. DR eggNOG; KOG1215; Eukaryota. DR eggNOG; KOG3511; Eukaryota. DR GeneTree; ENSGT01030000234563; -. DR HOGENOM; CLU_001389_0_0_1; -. DR InParanoid; Q92673; -. DR OMA; LCPDGME; -. DR OrthoDB; 443634at2759; -. DR PAN-GO; Q92673; 5 GO annotations based on evolutionary models. DR PhylomeDB; Q92673; -. DR PathwayCommons; Q92673; -. DR Reactome; R-HSA-977225; Amyloid fiber formation. DR SignaLink; Q92673; -. DR SIGNOR; Q92673; -. DR Agora; ENSG00000137642; -. DR BioGRID-ORCS; 6653; 18 hits in 1151 CRISPR screens. DR ChiTaRS; SORL1; human. DR EvolutionaryTrace; Q92673; -. DR GenomeRNAi; 6653; -. DR Pharos; Q92673; Tbio. DR PRO; PR:Q92673; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; Q92673; protein. DR Bgee; ENSG00000137642; Expressed in frontal pole and 206 other cell types or tissues. DR ExpressionAtlas; Q92673; baseline and differential. DR GO; GO:0009986; C:cell surface; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IEA:GOC. DR GO; GO:0005769; C:early endosome; IDA:UniProtKB. DR GO; GO:0031901; C:early endosome membrane; IDA:UniProt. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005768; C:endosome; IDA:UniProtKB. DR GO; GO:0010008; C:endosome membrane; TAS:Reactome. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0031985; C:Golgi cisterna; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0005771; C:multivesicular body; IDA:UniProtKB. DR GO; GO:0032585; C:multivesicular body membrane; IEA:UniProtKB-SubCell. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0005641; C:nuclear envelope lumen; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0097356; C:perinucleolar compartment; IEA:Ensembl. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0055037; C:recycling endosome; IMP:Alzheimers_University_of_Toronto. DR GO; GO:0055038; C:recycling endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005802; C:trans-Golgi network; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0030658; C:transport vesicle membrane; IEA:UniProtKB-SubCell. DR GO; GO:0001540; F:amyloid-beta binding; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0019828; F:aspartic-type endopeptidase inhibitor activity; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0030169; F:low-density lipoprotein particle binding; IPI:BHF-UCL. DR GO; GO:0005041; F:low-density lipoprotein particle receptor activity; TAS:ARUK-UCL. DR GO; GO:0042923; F:neuropeptide binding; IPI:UniProtKB. DR GO; GO:0140318; F:protein transporter activity; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0031267; F:small GTPase binding; IPI:Alzheimers_University_of_Toronto. DR GO; GO:0004888; F:transmembrane signaling receptor activity; IDA:UniProtKB. DR GO; GO:1990845; P:adaptive thermogenesis; ISS:UniProtKB. DR GO; GO:0016477; P:cell migration; IEA:Ensembl. DR GO; GO:0002024; P:diet induced thermogenesis; ISS:UniProtKB. DR GO; GO:0099638; P:endosome to plasma membrane protein transport; IEA:Ensembl. DR GO; GO:0038020; P:insulin receptor recycling; IDA:UniProtKB. DR GO; GO:1902992; P:negative regulation of amyloid precursor protein catabolic process; IDA:Alzheimers_University_of_Toronto. DR GO; GO:1902430; P:negative regulation of amyloid-beta formation; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; ISS:UniProtKB. DR GO; GO:1902997; P:negative regulation of neurofibrillary tangle assembly; ISS:Alzheimers_University_of_Toronto. DR GO; GO:0050768; P:negative regulation of neurogenesis; ISS:Alzheimers_University_of_Toronto. DR GO; GO:0031333; P:negative regulation of protein-containing complex assembly; IMP:Alzheimers_University_of_Toronto. DR GO; GO:0010897; P:negative regulation of triglyceride catabolic process; ISS:UniProtKB. DR GO; GO:0007218; P:neuropeptide signaling pathway; IDA:UniProtKB. DR GO; GO:1904179; P:positive regulation of adipose tissue development; IDA:UniProtKB. DR GO; GO:1902955; P:positive regulation of early endosome to recycling endosome transport; IMP:Alzheimers_University_of_Toronto. DR GO; GO:2001137; P:positive regulation of endocytic recycling; IMP:Alzheimers_University_of_Toronto. DR GO; GO:1902953; P:positive regulation of ER to Golgi vesicle-mediated transport; IMP:Alzheimers_University_of_Toronto. DR GO; GO:1900168; P:positive regulation of glial cell-derived neurotrophic factor production; IDA:UniProtKB. DR GO; GO:0046628; P:positive regulation of insulin receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0045732; P:positive regulation of protein catabolic process; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0070863; P:positive regulation of protein exit from endoplasmic reticulum; IMP:Alzheimers_University_of_Toronto. DR GO; GO:1902966; P:positive regulation of protein localization to early endosome; IMP:Alzheimers_University_of_Toronto. DR GO; GO:0006892; P:post-Golgi vesicle-mediated transport; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0034067; P:protein localization to Golgi apparatus; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0045053; P:protein retention in Golgi apparatus; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0006605; P:protein targeting; IDA:UniProtKB. DR GO; GO:0006622; P:protein targeting to lysosome; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0006898; P:receptor-mediated endocytosis; IDA:UniProtKB. DR GO; GO:0014910; P:regulation of smooth muscle cell migration; IDA:UniProtKB. DR GO; GO:0042147; P:retrograde transport, endosome to Golgi; IDA:UniProt. DR CDD; cd00063; FN3; 5. DR CDD; cd00112; LDLa; 11. DR FunFam; 4.10.400.10:FF:000006; Putative low-density lipoprotein receptor; 1. DR FunFam; 2.130.10.10:FF:000303; Sortilin related receptor 1; 1. DR FunFam; 2.60.40.10:FF:000404; Sortilin related receptor 1; 1. DR FunFam; 2.60.40.10:FF:000416; Sortilin related receptor 1; 1. DR FunFam; 2.60.40.10:FF:000461; Sortilin related receptor 1; 1. DR FunFam; 2.60.40.10:FF:001616; Sortilin related receptor 1; 1. DR FunFam; 4.10.400.10:FF:000027; Sortilin related receptor 1; 1. DR FunFam; 4.10.400.10:FF:000030; Sortilin related receptor 1; 1. DR FunFam; 4.10.400.10:FF:000036; Sortilin related receptor 1; 1. DR FunFam; 4.10.400.10:FF:000037; Sortilin related receptor 1; 1. DR FunFam; 4.10.400.10:FF:000039; Sortilin related receptor 1; 1. DR FunFam; 4.10.400.10:FF:000041; Sortilin related receptor 1; 1. DR FunFam; 4.10.400.10:FF:000048; Sortilin related receptor 1; 1. DR FunFam; 4.10.400.10:FF:000052; Sortilin related receptor 1; 1. DR FunFam; 4.10.400.10:FF:000060; Sortilin related receptor 1; 1. DR FunFam; 2.10.70.80:FF:000002; Sortilin-related receptor isoform A; 1. DR FunFam; 2.120.10.30:FF:000021; Sortilin-related receptor isoform A; 1. DR FunFam; 3.30.60.270:FF:000002; Sortilin-related receptor isoform A; 1. DR FunFam; 4.10.400.10:FF:000033; Sortilin-related receptor isoform A; 1. DR Gene3D; 2.10.70.80; -; 1. DR Gene3D; 3.30.60.270; -; 1. DR Gene3D; 2.60.40.10; Immunoglobulins; 3. DR Gene3D; 4.10.400.10; Low-density Lipoprotein Receptor; 11. DR Gene3D; 2.120.10.30; TolB, C-terminal domain; 1. DR Gene3D; 2.130.10.10; YVTN repeat-like/Quinoprotein amine dehydrogenase; 1. DR InterPro; IPR011042; 6-blade_b-propeller_TolB-like. DR InterPro; IPR003961; FN3_dom. DR InterPro; IPR036116; FN3_sf. DR InterPro; IPR057841; FN3_SORL1. DR InterPro; IPR013783; Ig-like_fold. DR InterPro; IPR036055; LDL_receptor-like_sf. DR InterPro; IPR023415; LDLR_class-A_CS. DR InterPro; IPR000033; LDLR_classB_rpt. DR InterPro; IPR002172; LDrepeatLR_classA_rpt. DR InterPro; IPR031777; Sortilin_C. DR InterPro; IPR031778; Sortilin_N. DR InterPro; IPR006581; VPS10. DR InterPro; IPR050310; VPS10-sortilin. DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom_sf. DR PANTHER; PTHR12106; SORTILIN RELATED; 1. DR PANTHER; PTHR12106:SF27; SORTILIN-RELATED RECEPTOR; 1. DR Pfam; PF00041; fn3; 3. DR Pfam; PF25814; fn3_SORL1; 1. DR Pfam; PF00057; Ldl_recept_a; 10. DR Pfam; PF00058; Ldl_recept_b; 2. DR Pfam; PF15902; Sortilin-Vps10; 1. DR Pfam; PF15901; Sortilin_C; 1. DR PRINTS; PR00261; LDLRECEPTOR. DR SMART; SM00060; FN3; 6. DR SMART; SM00192; LDLa; 11. DR SMART; SM00135; LY; 5. DR SMART; SM00602; VPS10; 1. DR SUPFAM; SSF49265; Fibronectin type III; 3. DR SUPFAM; SSF57424; LDL receptor-like module; 11. DR SUPFAM; SSF110296; Oligoxyloglucan reducing end-specific cellobiohydrolase; 2. DR SUPFAM; SSF63825; YWTD domain; 1. DR PROSITE; PS01186; EGF_2; 1. DR PROSITE; PS50853; FN3; 4. DR PROSITE; PS01209; LDLRA_1; 10. DR PROSITE; PS50068; LDLRA_2; 11. DR PROSITE; PS51120; LDLRB; 5. DR PROSITE; PS52072; VPS10P; 1. PE 1: Evidence at protein level; KW 3D-structure; Alzheimer disease; Amyloidosis; Cell membrane; KW Cleavage on pair of basic residues; Cytoplasmic vesicle; KW Direct protein sequencing; Disease variant; Disulfide bond; KW EGF-like domain; Endocytosis; Endoplasmic reticulum; Endosome; KW Glycoprotein; Golgi apparatus; Membrane; Neurodegeneration; Phosphoprotein; KW Protein transport; Proteomics identification; Receptor; Reference proteome; KW Repeat; Secreted; Signal; Transmembrane; Transmembrane helix; Transport. FT SIGNAL 1..28 FT /evidence="ECO:0000255" FT PROPEP 29..81 FT /note="Removed in mature form" FT /evidence="ECO:0000269|PubMed:8940146" FT /id="PRO_0000033164" FT CHAIN 82..2214 FT /note="Sortilin-related receptor" FT /id="PRO_0000033165" FT TOPO_DOM 82..2137 FT /note="Lumenal" FT /evidence="ECO:0000255" FT TRANSMEM 2138..2158 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 2159..2214 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 91..754 FT /note="Vps10p" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01417" FT REPEAT 136..147 FT /note="BNR 1" FT REPEAT 232..243 FT /note="BNR 2" FT REPEAT 441..452 FT /note="BNR 3" FT REPEAT 521..532 FT /note="BNR 4" FT REPEAT 562..573 FT /note="BNR 5" FT REPEAT 800..843 FT /note="LDL-receptor class B 1" FT REPEAT 844..887 FT /note="LDL-receptor class B 2" FT REPEAT 888..932 FT /note="LDL-receptor class B 3" FT REPEAT 933..970 FT /note="LDL-receptor class B 4" FT REPEAT 971..1013 FT /note="LDL-receptor class B 5" FT DOMAIN 1026..1072 FT /note="EGF-like" FT DOMAIN 1076..1114 FT /note="LDL-receptor class A 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1115..1155 FT /note="LDL-receptor class A 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1156..1194 FT /note="LDL-receptor class A 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1198..1236 FT /note="LDL-receptor class A 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1238..1272 FT /note="LDL-receptor class A 5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1273..1317 FT /note="LDL-receptor class A 6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1323..1361 FT /note="LDL-receptor class A 7" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1366..1405 FT /note="LDL-receptor class A 8" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1417..1455 FT /note="LDL-receptor class A 9" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1469..1508 FT /note="LDL-receptor class A 10" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1512..1551 FT /note="LDL-receptor class A 11" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1557..1649 FT /note="Fibronectin type-III 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT DOMAIN 1653..1745 FT /note="Fibronectin type-III 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT DOMAIN 1749..1844 FT /note="Fibronectin type-III 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT DOMAIN 1843..1927 FT /note="Fibronectin type-III 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT DOMAIN 1934..2029 FT /note="Fibronectin type-III 5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT DOMAIN 2030..2118 FT /note="Fibronectin type-III 6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT REGION 91..617 FT /note="10-bladed beta-propeller" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01417" FT REGION 625..675 FT /note="10CCa cysteine-knot" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01417" FT REGION 677..754 FT /note="10CCb cysteine-knot" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01417" FT REGION 2190..2214 FT /note="Required for efficient Golgi apparatus - endosome FT sorting" FT /evidence="ECO:0000269|PubMed:17646382" FT REGION 2201..2214 FT /note="Required for interaction with GGA1 and GGA2" FT /evidence="ECO:0000269|PubMed:11821067" FT MOTIF 63..65 FT /note="Cell attachment site" FT /evidence="ECO:0000255" FT MOTIF 2161..2164 FT /note="Potential nuclear localization signal for the C- FT terminal fragment generated by PSEN1" FT /evidence="ECO:0000305|PubMed:16531402" FT MOTIF 2172..2177 FT /note="Endocytosis signal" FT /evidence="ECO:0000255" FT MOTIF 2208..2212 FT /note="DXXLL motif involved in the interaction with GGA1" FT /evidence="ECO:0000269|PubMed:20015111" FT MOD_RES 114 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 2206 FT /note="Phosphoserine; by ROCK2" FT /evidence="ECO:0000269|PubMed:21147781" FT CARBOHYD 99 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218" FT CARBOHYD 158 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 368 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 430 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 616 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 674 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 818 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 871 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1035 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1068 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1164 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1191 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1246 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1367 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1458 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1608 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1706 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1733 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218" FT CARBOHYD 1809 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1854 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1894 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1986 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 2010 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218" FT CARBOHYD 2054 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 2069 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 2076 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218" FT CARBOHYD 2092 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218" FT DISULFID 467..473 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01417" FT DISULFID 625..660 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01417" FT DISULFID 643..675 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01417" FT DISULFID 677..736 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01417" FT DISULFID 684..699 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01417" FT DISULFID 716..752 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01417" FT DISULFID 1078..1090 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1085..1103 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1097..1112 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1117..1131 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1125..1144 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1138..1153 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1158..1170 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1165..1183 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1177..1192 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1199..1211 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1206..1224 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1218..1235 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1239..1249 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1244..1262 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1256..1271 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1275..1289 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1283..1302 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1296..1315 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1325..1337 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1332..1350 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1344..1359 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1368..1381 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1376..1394 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1388..1403 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1419..1431 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1426..1444 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1438..1453 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1471..1484 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1478..1497 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1491..1506 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1514..1527 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1521..1540 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1534..1549 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT VARIANT 120 FT /note="L -> S (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036371" FT VARIANT 141 FT /note="Y -> C (in AD; uncertain significance)" FT /evidence="ECO:0000269|PubMed:22472873" FT /id="VAR_070012" FT VARIANT 511 FT /note="G -> R (in AD; uncertain significance; loss of FT interaction with APP amyloid-beta peptides, hence reduced FT turnover of APP amyloid-beta peptides in cells)" FT /evidence="ECO:0000269|PubMed:22472873, FT ECO:0000269|PubMed:24523320" FT /id="VAR_070013" FT VARIANT 528 FT /note="A -> T (in dbSNP:rs2298813)" FT /evidence="ECO:0000269|PubMed:18407551" FT /id="VAR_020360" FT VARIANT 924 FT /note="N -> S (in AD; uncertain significance; FT dbSNP:rs377498269)" FT /evidence="ECO:0000269|PubMed:22472873" FT /id="VAR_070014" FT VARIANT 1074 FT /note="Q -> E (in dbSNP:rs1699107)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:8940146, ECO:0000269|PubMed:9157966, FT ECO:0000269|Ref.4" FT /id="VAR_034508" FT VARIANT 1358 FT /note="N -> S (in AD; uncertain significance; FT dbSNP:rs747306346)" FT /evidence="ECO:0000269|PubMed:22472873" FT /id="VAR_070015" FT VARIANT 1581 FT /note="M -> L (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036372" FT VARIANT 1681 FT /note="G -> D (in AD; uncertain significance; FT dbSNP:rs1565352546)" FT /evidence="ECO:0000269|PubMed:22472873" FT /id="VAR_070016" FT VARIANT 1967 FT /note="V -> I (in dbSNP:rs1792120)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:8940146, ECO:0000269|PubMed:9157966, FT ECO:0000269|Ref.4" FT /id="VAR_034509" FT VARIANT 1972 FT /note="L -> V (in a colorectal cancer sample; somatic FT mutation; dbSNP:rs766895956)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036373" FT MUTAGEN 78..81 FT /note="RRKR->GRKG: Loss of propeptide cleavage." FT /evidence="ECO:0000269|PubMed:11294867" FT MUTAGEN 2163..2164 FT /note="RR->AA: Affects the nuclear location of the C- FT terminal fragment generated by PSEN1." FT /evidence="ECO:0000269|PubMed:16531402" FT MUTAGEN 2172..2177 FT /note="FANSHY->AAASHA: No effect on endocytosis." FT /evidence="ECO:0000269|PubMed:17646382" FT MUTAGEN 2190..2214 FT /note="Missing: Strong reduction in Golgi apparatus FT - endosome sorting. Loss of interaction with AP-1 complex." FT /evidence="ECO:0000269|PubMed:17646382" FT MUTAGEN 2190..2198 FT /note="DDLGEDDED->AALGAAAAA: Loss of interaction with GGA1 FT and PACS1. No effect on interaction with APP. Affects FT subcellular location, increasing localization at the cell FT surface, possibly due to drastically decreased endocytosis. FT Impaired Golgi apparatus - endosome sorting. Increased FT amyloidogenic APP processing by beta-secretase, resulting FT in increased levels of soluble APP-beta and amyloid-beta FT protein 40 and 42. Loss of APOA5 internalization." FT /evidence="ECO:0000269|PubMed:17646382, FT ECO:0000269|PubMed:17855360, ECO:0000269|PubMed:18603531" FT MUTAGEN 2190..2191 FT /note="DD->AA: No effect on the interaction with HSPA12A." FT /evidence="ECO:0000269|PubMed:30679749" FT MUTAGEN 2194..2198 FT /note="EDDED->AAAAA: Strong decrease in interaction with FT HSPA12A." FT /evidence="ECO:0000269|PubMed:30679749" FT MUTAGEN 2201..2202 FT /note="MI->AA: No effect on endocytosis. Decreased Golgi FT apparatus - endosome sorting." FT /evidence="ECO:0000269|PubMed:17646382" FT MUTAGEN 2203..2204 FT /note="TG->AA: No effect on the interaction with HSPA12A." FT /evidence="ECO:0000269|PubMed:30679749" FT MUTAGEN 2205..2206 FT /note="FS->AA: No effect on the interaction with HSPA12A." FT /evidence="ECO:0000269|PubMed:30679749" FT MUTAGEN 2207..2208 FT /note="DD->AA: Strong decrease in interaction with FT HSPA12A." FT /evidence="ECO:0000269|PubMed:30679749" FT MUTAGEN 2208..2211 FT /note="DVPM->AVPA: Loss of interaction with GGA1 and PACS1. FT No effect on interaction with APP. Affects subcellular FT location, by causing increased localization to recycling FT endosomes. Increased APP processing by alpha-secretase, FT resulting in increased levels of soluble APP-alpha and C83 FT APP fragments. Decreased APP processing by beta-secretase, FT resulting in reduced levels of C99 APP fragment." FT /evidence="ECO:0000269|PubMed:17855360" FT MUTAGEN 2209..2210 FT /note="VP->AA: No effect on the interaction with HSPA12A." FT /evidence="ECO:0000269|PubMed:30679749" FT MUTAGEN 2211..2214 FT /note="Missing: No effect on endocytosis. Affects LPL FT sorting to endosomes." FT /evidence="ECO:0000269|PubMed:17646382, FT ECO:0000269|PubMed:21385844" FT STRAND 48..51 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 91..98 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 103..109 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 117..122 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 125..128 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 133..140 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 145..147 FT /evidence="ECO:0007829|PDB:3WSY" FT HELIX 149..151 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 164..169 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 177..192 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 198..201 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 207..211 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 219..223 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 230..236 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 242..253 FT /evidence="ECO:0007829|PDB:3WSX" FT TURN 256..258 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 264..268 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 271..273 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 275..282 FT /evidence="ECO:0007829|PDB:3WSX" FT HELIX 287..289 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 290..298 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 300..303 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 306..313 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 318..320 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 323..330 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 333..337 FT /evidence="ECO:0007829|PDB:3WSZ" FT STRAND 349..353 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 355..358 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 360..363 FT /evidence="ECO:0007829|PDB:3WSX" FT HELIX 366..368 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 369..374 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 377..379 FT /evidence="ECO:0007829|PDB:7VT0" FT STRAND 383..391 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 394..396 FT /evidence="ECO:0007829|PDB:3WSY" FT TURN 397..400 FT /evidence="ECO:0007829|PDB:3WSY" FT HELIX 402..405 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 407..409 FT /evidence="ECO:0007829|PDB:7VT0" FT STRAND 411..416 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 420..422 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 424..428 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 431..434 FT /evidence="ECO:0007829|PDB:3WSY" FT HELIX 435..437 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 439..445 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 451..453 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 460..462 FT /evidence="ECO:0007829|PDB:3WSY" FT HELIX 469..471 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 473..479 FT /evidence="ECO:0007829|PDB:3WSX" FT HELIX 480..485 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 488..490 FT /evidence="ECO:0007829|PDB:7VT0" FT STRAND 492..495 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 498..500 FT /evidence="ECO:0007829|PDB:7VT0" FT STRAND 504..510 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 512..514 FT /evidence="ECO:0007829|PDB:7VT0" FT STRAND 519..525 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 528..530 FT /evidence="ECO:0007829|PDB:7VT0" FT STRAND 531..536 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 538..543 FT /evidence="ECO:0007829|PDB:3WSX" FT HELIX 544..546 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 548..553 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 560..566 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 572..575 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 577..579 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 581..588 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 590..592 FT /evidence="ECO:0007829|PDB:7VT0" FT STRAND 596..602 FT /evidence="ECO:0007829|PDB:3WSX" FT TURN 604..607 FT /evidence="ECO:0007829|PDB:3WSZ" FT STRAND 610..616 FT /evidence="ECO:0007829|PDB:3WSX" FT HELIX 618..621 FT /evidence="ECO:0007829|PDB:3WSX" FT HELIX 627..629 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 630..633 FT /evidence="ECO:0007829|PDB:3WSX" FT HELIX 635..637 FT /evidence="ECO:0007829|PDB:3WSY" FT TURN 638..641 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 647..654 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 670..674 FT /evidence="ECO:0007829|PDB:3WSX" FT HELIX 679..681 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 682..684 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 688..690 FT /evidence="ECO:0007829|PDB:3WSX" FT HELIX 694..696 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 699..701 FT /evidence="ECO:0007829|PDB:3WSX" FT HELIX 703..705 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 722..724 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 727..730 FT /evidence="ECO:0007829|PDB:3WSX" FT TURN 740..745 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 748..750 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 1655..1660 FT /evidence="ECO:0007829|PDB:2DM4" FT STRAND 1669..1674 FT /evidence="ECO:0007829|PDB:2DM4" FT STRAND 1683..1692 FT /evidence="ECO:0007829|PDB:2DM4" FT STRAND 1699..1710 FT /evidence="ECO:0007829|PDB:2DM4" FT STRAND 1718..1729 FT /evidence="ECO:0007829|PDB:2DM4" FT STRAND 1731..1734 FT /evidence="ECO:0007829|PDB:2DM4" FT STRAND 1738..1741 FT /evidence="ECO:0007829|PDB:2DM4" SQ SEQUENCE 2214 AA; 248426 MW; 4C215BB33E65C0B2 CRC64; MATRSSRRES RLPFLFTLVA LLPPGALCEV WTQRLHGGSA PLPQDRGFLV VQGDPRELRL WARGDARGAS RADEKPLRRK RSAALQPEPI KVYGQVSLND SHNQMVVHWA GEKSNVIVAL ARDSLALARP KSSDVYVSYD YGKSFKKISD KLNFGLGNRS EAVIAQFYHS PADNKRYIFA DAYAQYLWIT FDFCNTLQGF SIPFRAADLL LHSKASNLLL GFDRSHPNKQ LWKSDDFGQT WIMIQEHVKS FSWGIDPYDK PNTIYIERHE PSGYSTVFRS TDFFQSRENQ EVILEEVRDF QLRDKYMFAT KVVHLLGSEQ QSSVQLWVSF GRKPMRAAQF VTRHPINEYY IADASEDQVF VCVSHSNNRT NLYISEAEGL KFSLSLENVL YYSPGGAGSD TLVRYFANEP FADFHRVEGL QGVYIATLIN GSMNEENMRS VITFDKGGTW EFLQAPAFTG YGEKINCELS QGCSLHLAQR LSQLLNLQLR RMPILSKESA PGLIIATGSV GKNLASKTNV YISSSAGARW REALPGPHYY TWGDHGGIIT AIAQGMETNE LKYSTNEGET WKTFIFSEKP VFVYGLLTEP GEKSTVFTIF GSNKENVHSW LILQVNATDA LGVPCTENDY KLWSPSDERG NECLLGHKTV FKRRTPHATC FNGEDFDRPV VVSNCSCTRE DYECDFGFKM SEDLSLEVCV PDPEFSGKSY SPPVPCPVGS TYRRTRGYRK ISGDTCSGGD VEARLEGELV PCPLAEENEF ILYAVRKSIY RYDLASGATE QLPLTGLRAA VALDFDYEHN CLYWSDLALD VIQRLCLNGS TGQEVIINSG LETVEALAFE PLSQLLYWVD AGFKKIEVAN PDGDFRLTIV NSSVLDRPRA LVLVPQEGVM FWTDWGDLKP GIYRSNMDGS AAYHLVSEDV KWPNGISVDD QWIYWTDAYL ECIERITFSG QQRSVILDNL PHPYAIAVFK NEIYWDDWSQ LSIFRASKYS GSQMEILANQ LTGLMDMKIF YKGKNTGSNA CVPRPCSLLC LPKANNSRSC RCPEDVSSSV LPSGDLMCDC PQGYQLKNNT CVKQENTCLR NQYRCSNGNC INSIWWCDFD NDCGDMSDER NCPTTICDLD TQFRCQESGT CIPLSYKCDL EDDCGDNSDE SHCEMHQCRS DEYNCSSGMC IRSSWVCDGD NDCRDWSDEA NCTAIYHTCE ASNFQCRNGH CIPQRWACDG DTDCQDGSDE DPVNCEKKCN GFRCPNGTCI PSSKHCDGLR DCSDGSDEQH CEPLCTHFMD FVCKNRQQCL FHSMVCDGII QCRDGSDEDA AFAGCSQDPE FHKVCDEFGF QCQNGVCISL IWKCDGMDDC GDYSDEANCE NPTEAPNCSR YFQFRCENGH CIPNRWKCDR ENDCGDWSDE KDCGDSHILP FSTPGPSTCL PNYYRCSSGT CVMDTWVCDG YRDCADGSDE EACPLLANVT AASTPTQLGR CDRFEFECHQ PKTCIPNWKR CDGHQDCQDG RDEANCPTHS TLTCMSREFQ CEDGEACIVL SERCDGFLDC SDESDEKACS DELTVYKVQN LQWTADFSGD VTLTWMRPKK MPSASCVYNV YYRVVGESIW KTLETHSNKT NTVLKVLKPD TTYQVKVQVQ CLSKAHNTND FVTLRTPEGL PDAPRNLQLS LPREAEGVIV GHWAPPIHTH GLIREYIVEY SRSGSKMWAS QRAASNFTEI KNLLVNTLYT VRVAAVTSRG IGNWSDSKSI TTIKGKVIPP PDIHIDSYGE NYLSFTLTME SDIKVNGYVV NLFWAFDTHK QERRTLNFRG SILSHKVGNL TAHTSYEISA WAKTDLGDSP LAFEHVMTRG VRPPAPSLKA KAINQTAVEC TWTGPRNVVY GIFYATSFLD LYRNPKSLTT SLHNKTVIVS KDEQYLFLVR VVVPYQGPSS DYVVVKMIPD SRLPPRHLHV VHTGKTSVVI KWESPYDSPD QDLLYAVAVK DLIRKTDRSY KVKSRNSTVE YTLNKLEPGG KYHIIVQLGN MSKDSSIKIT TVSLSAPDAL KIITENDHVL LFWKSLALKE KHFNESRGYE IHMFDSAMNI TAYLGNTTDN FFKISNLKMG HNYTFTVQAR CLFGNQICGE PAILLYDELG SGADASATQA ARSTDVAAVV VPILFLILLS LGVGFAILYT KHRRLQSSFT AFANSHYSSR LGSAIFSSGD DLGEDDEDAP MITGFSDDVP MVIA // ID SPTC1_HUMAN Reviewed; 473 AA. AC O15269; A8K681; Q5VWB4; Q96IX6; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 01-JAN-1998, sequence version 1. DT 28-JAN-2026, entry version 218. DE RecName: Full=Serine palmitoyltransferase 1; DE EC=2.3.1.50 {ECO:0000269|PubMed:19416851}; DE AltName: Full=Long chain base biosynthesis protein 1; DE Short=LCB 1; DE AltName: Full=Serine-palmitoyl-CoA transferase 1; DE Short=SPT 1; DE Short=SPT1; GN Name=SPTLC1; Synonyms=LCB1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Kidney; RX PubMed=9363775; DOI=10.1111/j.1432-1033.1997.00239.x; RA Weiss B., Stoffel W.; RT "Human and murine serine-palmitoyl-CoA transferase. Cloning, expression and RT characterization of the key enzyme in sphingolipid synthesis."; RL Eur. J. Biochem. 249:239-247(1997). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), AND VARIANTS HSAN1A RP TRP-133; TYR-133 AND ASP-144. RX PubMed=11242114; DOI=10.1038/85879; RA Dawkins J.L., Hulme D.J., Brahmbhatt S.B., Auer-Grumbach M., RA Nicholson G.A.; RT "Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base RT subunit-1, cause hereditary sensory neuropathy type I."; RL Nat. Genet. 27:309-312(2001). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Placenta; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164053; DOI=10.1038/nature02465; RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L., RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E., RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M., RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J., RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P., RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S., RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E., RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D., RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E., RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K., RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S., RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J., RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E., RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V., RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S., RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K., RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J., RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L., RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M., RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J., RA Dunham I.; RT "DNA sequence and analysis of human chromosome 9."; RL Nature 429:369-374(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP TISSUE SPECIFICITY. RX PubMed=17023427; DOI=10.1074/jbc.m608066200; RA Hornemann T., Richard S., Ruetti M.F., Wei Y., von Eckardstein A.; RT "Cloning and initial characterization of a new subunit for mammalian RT serine-palmitoyltransferase."; RL J. Biol. Chem. 281:37275-37281(2006). RN [8] RP FUNCTION. RX PubMed=19648650; DOI=10.1074/jbc.m109.023192; RA Hornemann T., Penno A., Ruetti M.F., Ernst D., Kivrak-Pfiffner F., RA Rohrer L., von Eckardstein A.; RT "The SPTLC3 subunit of serine palmitoyltransferase generates short chain RT sphingoid bases."; RL J. Biol. Chem. 284:26322-26330(2009). RN [9] RP FUNCTION, CATALYTIC ACTIVITY, IDENTIFICATION IN THE SPT COMPLEX, AND RP INTERACTION WITH SPTSSA AND SPTSSB. RX PubMed=19416851; DOI=10.1073/pnas.0811269106; RA Han G., Gupta S.D., Gable K., Niranjanakumari S., Moitra P., Eichler F., RA Brown R.H. Jr., Harmon J.M., Dunn T.M.; RT "Identification of small subunits of mammalian serine palmitoyltransferase RT that confer distinct acyl-CoA substrate specificities."; RL Proc. Natl. Acad. Sci. U.S.A. 106:8186-8191(2009). RN [10] RP BIOPHYSICOCHEMICAL PROPERTIES, AND CHARACTERIZATION OF VARIANT HSAN1A RP TRP-133. RX PubMed=20504773; DOI=10.1074/jbc.m110.122259; RA Gable K., Gupta S.D., Han G., Niranjanakumari S., Harmon J.M., Dunn T.M.; RT "A disease-causing mutation in the active site of serine RT palmitoyltransferase causes catalytic promiscuity."; RL J. Biol. Chem. 285:22846-22852(2010). RN [11] RP INTERACTION WITH ORMDL3. RX PubMed=20182505; DOI=10.1038/nature08787; RA Breslow D.K., Collins S.R., Bodenmiller B., Aebersold R., Simons K., RA Shevchenko A., Ejsing C.S., Weissman J.S.; RT "Orm family proteins mediate sphingolipid homeostasis."; RL Nature 463:1048-1053(2010). RN [12] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [13] RP INDUCTION IN ALZHEIMER DISEASE. RX PubMed=21994399; DOI=10.1523/jneurosci.3883-11.2011; RA Geekiyanage H., Chan C.; RT "MicroRNA-137/181c regulates serine palmitoyltransferase and in turn RT amyloid beta, novel targets in sporadic Alzheimer's disease."; RL J. Neurosci. 31:14820-14830(2011). RN [14] RP PHOSPHORYLATION AT TYR-164, AND MUTAGENESIS OF TYR-164. RX PubMed=23629659; DOI=10.1074/jbc.m112.409185; RA Taouji S., Higa A., Delom F., Palcy S., Mahon F.X., Pasquet J.M., Bosse R., RA Segui B., Chevet E.; RT "Phosphorylation of serine palmitoyltransferase long chain-1 (SPTLC1) on RT tyrosine 164 inhibits its activity and promotes cell survival."; RL J. Biol. Chem. 288:17190-17201(2013). RN [15] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [16] RP REGULATION OF SPT COMPLEX ACTIVITY BY ORMDL PROTEINS IN THE PRESENCE OF RP CERAMIDES. RX PubMed=30700557; DOI=10.1074/jbc.ra118.007291; RA Davis D.L., Gable K., Suemitsu J., Dunn T.M., Wattenberg B.W.; RT "The ORMDL/Orm-serine palmitoyltransferase (SPT) complex is directly RT regulated by ceramide: Reconstitution of SPT regulation in isolated RT membranes."; RL J. Biol. Chem. 294:5146-5156(2019). RN [17] RP FUNCTION. RX PubMed=36170811; DOI=10.1016/j.celrep.2022.111415; RA Spears M.E., Lee N., Hwang S., Park S.J., Carlisle A.E., Li R., Doshi M.B., RA Armando A.M., Gao J., Simin K., Zhu L.J., Greer P.L., Quehenberger O., RA Torres E.M., Kim D.; RT "De novo sphingolipid biosynthesis necessitates detoxification in cancer RT cells."; RL Cell Rep. 40:111415-111415(2022). RN [18] {ECO:0007744|PDB:7K0I, ECO:0007744|PDB:7K0J, ECO:0007744|PDB:7K0K, ECO:0007744|PDB:7K0L, ECO:0007744|PDB:7K0M, ECO:0007744|PDB:7K0N, ECO:0007744|PDB:7K0O, ECO:0007744|PDB:7K0P, ECO:0007744|PDB:7K0Q} RP STRUCTURE BY ELECTRON MICROSCOPY (2.60 ANGSTROMS) IN COMPLEX WITH SPTLC2; RP SPTSSA AND ORMDL3, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=33558761; DOI=10.1038/s41594-020-00551-9; RA Wang Y., Niu Y., Zhang Z., Gable K., Gupta S.D., Somashekarappa N., Han G., RA Zhao H., Myasnikov A.G., Kalathur R.C., Dunn T.M., Lee C.H.; RT "Structural insights into the regulation of human serine RT palmitoyltransferase complexes."; RL Nat. Struct. Mol. Biol. 28:240-248(2021). RN [19] {ECO:0007744|PDB:6M4N, ECO:0007744|PDB:6M4O, ECO:0007744|PDB:7CQI, ECO:0007744|PDB:7CQK} RP STRUCTURE BY ELECTRON MICROSCOPY (3.20 ANGSTROMS) IN COMPLEX WITH SPTLC2; RP SPTSSA AND ORMDL3, FUNCTION, AND MUTAGENESIS OF PHE-138; PHE-337 AND RP SER-338. RX PubMed=33558762; DOI=10.1038/s41594-020-00553-7; RA Li S., Xie T., Liu P., Wang L., Gong X.; RT "Structural insights into the assembly and substrate selectivity of human RT SPT-ORMDL3 complex."; RL Nat. Struct. Mol. Biol. 28:249-257(2021). RN [20] {ECO:0007744|PDB:7YIU, ECO:0007744|PDB:7YIY, ECO:0007744|PDB:7YJ1, ECO:0007744|PDB:7YJ2} RP STRUCTURE BY ELECTRON MICROSCOPY (2.70 ANGSTROMS) IN COMPLEX WITH SPTLC2; RP SPTSSA AND ORMDL3, CHARACTERIZATION OF VARIANTS ALS27 PHE-23; LEU-39 DEL RP AND 40-PHE-SER-41 DEL, AND ACTIVITY REGULATION. RX PubMed=37308477; DOI=10.1038/s41467-023-39274-y; RA Xie T., Liu P., Wu X., Dong F., Zhang Z., Yue J., Mahawar U., Farooq F., RA Vohra H., Fang Q., Liu W., Wattenberg B.W., Gong X.; RT "Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid RT homeostasis."; RL Nat. Commun. 14:3475-3475(2023). RN [21] RP VARIANT ALA-387. RX PubMed=15037712; DOI=10.1212/01.wnl.0000115388.10828.5c; RA Verhoeven K., Coen K., De Vriendt E., Jacobs A., Van Gerwen V., Smouts I., RA Pou-Serradell A., Martin J.-J., Timmerman V., De Jonghe P.; RT "SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type RT I."; RL Neurology 62:1001-1002(2004). RN [22] RP VARIANT LEU-151. RX PubMed=17060578; DOI=10.1212/01.wnl.0000240068.21499.f5; RA Meggouh F., Bienfait H.M.E., Weterman M.A.J., de Visser M., Baas F.; RT "Charcot-Marie-Tooth disease due to a de novo mutation of the RAB7 gene."; RL Neurology 67:1476-1478(2006). RN [23] RP VARIANT [LARGE SCALE ANALYSIS] TRP-239. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). RN [24] RP VARIANTS HSAN1A PHE-331 AND VAL-352, AND VARIANT ALA-387. RX PubMed=19651702; DOI=10.1093/brain/awp198; RA Rotthier A., Baets J., De Vriendt E., Jacobs A., Auer-Grumbach M., Levy N., RA Bonello-Palot N., Kilic S.S., Weis J., Nascimento A., Swinkels M., RA Kruyt M.C., Jordanova A., De Jonghe P., Timmerman V.; RT "Genes for hereditary sensory and autonomic neuropathies: a genotype- RT phenotype correlation."; RL Brain 132:2699-2711(2009). RN [25] RP CHARACTERIZATION OF VARIANTS HSAN1A TYR-133; TRP-133 AND ASP-144, RP CHARACTERIZATION OF VARIANT ALA-387, LACK OF ASSOCIATION OF VARIANT ALA-387 RP WITH HSAN1A, AND INTERACTION WITH SPTLC2. RX PubMed=19132419; DOI=10.1007/s10048-008-0168-7; RA Hornemann T., Penno A., Richard S., Nicholson G., van Dijk F.S., RA Rotthier A., Timmerman V., von Eckardstein A.; RT "A systematic comparison of all mutations in hereditary sensory neuropathy RT type I (HSAN I) reveals that the G387A mutation is not disease RT associated."; RL Neurogenetics 10:135-143(2009). RN [26] RP VARIANT HSAN1A PHE-331, CHARACTERIZATION OF VARIANTS HSAN1A TRP-133; RP PHE-331 AND VAL-352, AND SUBCELLULAR LOCATION. RX PubMed=21618344; DOI=10.1002/humu.21481; RA Rotthier A., Penno A., Rautenstrauss B., Auer-Grumbach M., Stettner G.M., RA Asselbergh B., Van Hoof K., Sticht H., Levy N., Timmerman V., Hornemann T., RA Janssens K.; RT "Characterization of two mutations in the SPTLC1 subunit of serine RT palmitoyltransferase associated with hereditary sensory and autonomic RT neuropathy type I."; RL Hum. Mutat. 32:E2211-E2225(2011). RN [27] RP VARIANT HSAN1A TRP-133, AND VARIANT GLY-310. RX PubMed=22302274; DOI=10.1007/s00415-011-6397-y; RA Davidson G.L., Murphy S.M., Polke J.M., Laura M., Salih M.A., Muntoni F., RA Blake J., Brandner S., Davies N., Horvath R., Price S., Donaghy M., RA Roberts M., Foulds N., Ramdharry G., Soler D., Lunn M.P., Manji H., RA Davis M.B., Houlden H., Reilly M.M.; RT "Frequency of mutations in the genes associated with hereditary sensory and RT autonomic neuropathy in a UK cohort."; RL J. Neurol. 259:1673-1685(2012). RN [28] RP INVOLVEMENT IN HSAN1A, VARIANT HSAN1A TYR-331, AND CHARACTERIZATION OF RP VARIANT HSAN1A TYR-331. RX PubMed=23454272; DOI=10.1016/j.ejmg.2013.02.002; RA Auer-Grumbach M., Bode H., Pieber T.R., Schabhuettl M., Fischer D., RA Seidl R., Graf E., Wieland T., Schuh R., Vacariu G., Grill F., RA Timmerman V., Strom T.M., Hornemann T.; RT "Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a RT distinct syndromic phenotype."; RL Eur. J. Med. Genet. 56:266-269(2013). RN [29] RP VARIANT HSAN1A PHE-331. RX PubMed=24247255; DOI=10.3892/mmr.2013.1808; RA Suh B.C., Hong Y.B., Nakhro K., Nam S.H., Chung K.W., Choi B.O.; RT "Early-onset severe hereditary sensory and autonomic neuropathy type 1 with RT S331F SPTLC1 mutation."; RL Mol. Med. Report. 9:481-486(2014). RN [30] RP VARIANT HSAN1A ASP-144. RX PubMed=30420926; DOI=10.1155/2018/1898151; RA Ho K.W.D., Jerath N.U.; RT "V144D Mutation of SPTLC1 Can Present with Both Painful and Painless RT Phenotypes in Hereditary Sensory and Autonomic Neuropathies Type I."; RL Case Rep. Genet. 2018:1898151-1898151(2018). RN [31] RP INVOLVEMENT IN ALS27, AND VARIANTS ALS27 SER-20; LEU-39 DEL AND TYR-331. RX PubMed=34459874; DOI=10.1001/jamaneurol.2021.2598; RG FALS Sequencing Consortium; RG American Genome Center; RG International ALS Genomics Consortium; RG and ITALSGEN Consortium; RA Johnson J.O., Chia R., Miller D.E., Li R., Kumaran R., Abramzon Y., RA Alahmady N., Renton A.E., Topp S.D., Gibbs J.R., Cookson M.R., Sabir M.S., RA Dalgard C.L., Troakes C., Jones A.R., Shatunov A., Iacoangeli A., RA Al Khleifat A., Ticozzi N., Silani V., Gellera C., Blair I.P., RA Dobson-Stone C., Kwok J.B., Bonkowski E.S., Palvadeau R., Tienari P.J., RA Morrison K.E., Shaw P.J., Al-Chalabi A., Brown R.H. Jr., Calvo A., Mora G., RA Al-Saif H., Gotkine M., Leigh F., Chang I.J., Perlman S.J., Glass I., RA Scott A.I., Shaw C.E., Basak A.N., Landers J.E., Chio A., Crawford T.O., RA Smith B.N., Traynor B.J., Smith B.N., Ticozzi N., Fallini C., Gkazi A.S., RA Topp S.D., Scotter E.L., Kenna K.P., Keagle P., Tiloca C., Vance C., RA Troakes C., Colombrita C., King A., Pensato V., Castellotti B., Baas F., RA Ten Asbroek A.L.M.A., McKenna-Yasek D., McLaughlin R.L., Polak M., RA Asress S., Esteban-Perez J., Stevic Z., D'Alfonso S., Mazzini L., RA Comi G.P., Del Bo R., Ceroni M., Gagliardi S., Querin G., Bertolin C., RA van Rheenen W., Rademakers R., van Blitterswijk M., Lauria G., Duga S., RA Corti S., Cereda C., Corrado L., Soraru G., Williams K.L., Nicholson G.A., RA Blair I.P., Leblond-Manry C., Rouleau G.A., Hardiman O., Morrison K.E., RA Veldink J.H., van den Berg L.H., Al-Chalabi A., Pall H., Shaw P.J., RA Turner M.R., Talbot K., Taroni F., Garcia-Redondo A., Wu Z., Glass J.D., RA Gellera C., Ratti A., Brown R.H. Jr., Silani V., Shaw C.E., Landers J.E., RA Dalgard C.L., Adeleye A., Soltis A.R., Alba C., Viollet C., Bacikova D., RA Hupalo D.N., Sukumar G., Pollard H.B., Wilkerson M.D., Martinez E.M., RA Abramzon Y., Ahmed S., Arepalli S., Baloh R.H., Bowser R., Brady C.B., RA Brice A., Broach J., Campbell R.H., Camu W., Chia R., Cooper-Knock J., RA Ding J., Drepper C., Drory V.E., Dunckley T.L., Eicher J.D., England B.K., RA Faghri F., Feldman E., Floeter M.K., Fratta P., Geiger J.T., Gerhard G., RA Gibbs J.R., Gibson S.B., Glass J.D., Hardy J., Harms M.B., RA Heiman-Patterson T.D., Hernandez D.G., Jansson L., Kirby J., Kowall N.W., RA Laaksovirta H., Landeck N., Landi F., Le Ber I., Lumbroso S., RA MacGowan D.J.L., Maragakis N.J., Mora G., Mouzat K., Murphy N.A., RA Myllykangas L., Nalls M.A., Orrell R.W., Ostrow L.W., Pamphlett R., RA Pickering-Brown S., Pioro E.P., Pletnikova O., Pliner H.A., Pulst S.M., RA Ravits J.M., Renton A.E., Rivera A., Robberecht W., Rogaeva E., RA Rollinson S., Rothstein J.D., Scholz S.W., Sendtner M., Shaw P.J., RA Sidle K.C., Simmons Z., Singleton A.B., Smith N., Stone D.J., Tienari P.J., RA Troncoso J.C., Valori M., Van Damme P., Van Deerlin V.M., Van Den Bosch L., RA Zinman L., Landers J.E., Chio A., Traynor B.J., Angelocola S.M., RA Ausiello F.P., Barberis M., Bartolomei I., Battistini S., Bersano E., RA Bisogni G., Borghero G., Brunetti M., Cabona C., Calvo A., Canale F., RA Canosa A., Cantisani T.A., Capasso M., Caponnetto C., Cardinali P., RA Carrera P., Casale F., Chio A., Colletti T., Conforti F.L., Conte A., RA Conti E., Corbo M., Cuccu S., Dalla Bella E., D'Errico E., DeMarco G., RA Dubbioso R., Ferrarese C., Ferraro P.M., Filippi M., Fini N., Floris G., RA Fuda G., Gallone S., Gianferrari G., Giannini F., Grassano M., Greco L., RA Iazzolino B., Introna A., La Bella V., Lattante S., Lauria G., Liguori R., RA Logroscino G., Logullo F.O., Lunetta C., Mandich P., Mandrioli J., RA Manera U., Manganelli F., Marangi G., Marinou K., Marrosu M.G., RA Martinelli I., Messina S., Moglia C., Mora G., Mosca L., Murru M.R., RA Origone P., Passaniti C., Petrelli C., Petrucci A., Pozzi S., Pugliatti M., RA Quattrini A., Ricci C., Riolo G., Riva N., Russo M., Sabatelli M., RA Salamone P., Salivetto M., Salvi F., Santarelli M., Sbaiz L., Sideri R., RA Simone I., Simonini C., Spataro R., Tanel R., Tedeschi G., Ticca A., RA Torriello A., Tranquilli S., Tremolizzo L., Trojsi F., Vasta R., RA Vacchiano V., Vita G., Volanti P., Zollino M., Zucchi E.; RT "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic RT Lateral Sclerosis."; RL JAMA Neurol. 78:1236-1248(2021). RN [32] RP INVOLVEMENT IN ALS27, VARIANTS ALS27 SER-20; PHE-23; LEU-39 DEL AND RP 40-PHE-SER-41 DEL, CHARACTERIZATION OF VARIANTS ALS27 SER-20; PHE-23; RP LEU-39 DEL AND 40-PHE-SER-41 DEL, AND HOMEOSTATIC REGULATION BY ORMDL3 IN RP THE PRESENCE OF CERAMIDES. RX PubMed=34059824; DOI=10.1038/s41591-021-01346-1; RA Mohassel P., Donkervoort S., Lone M.A., Nalls M., Gable K., Gupta S.D., RA Foley A.R., Hu Y., Saute J.A.M., Moreira A.L., Kok F., Introna A., RA Logroscino G., Grunseich C., Nickolls A.R., Pourshafie N., Neuhaus S.B., RA Saade D., Gangfuss A., Koelbel H., Piccus Z., Le Pichon C.E., Fiorillo C., RA Ly C.V., Toepf A., Brady L., Specht S., Zidell A., Pedro H., Mittelmann E., RA Thomas F.P., Chao K.R., Konersman C.G., Cho M.T., Brandt T., Straub V., RA Connolly A.M., Schara U., Roos A., Tarnopolsky M., Hoeke A., Brown R.H., RA Lee C.H., Hornemann T., Dunn T.M., Boennemann C.G.; RT "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid RT synthesis."; RL Nat. Med. 27:1197-1204(2021). RN [33] RP INVOLVEMENT IN ALS27, AND VARIANT ALS27 ARG-38. RX PubMed=36204986; DOI=10.1080/21678421.2022.2096409; RA Liu X., He J., Yu W., Fan D.; RT "A de novo c.113 T > C: p.L38R mutation of SPTLC1: case report of a girl RT with sporadic juvenile amyotrophic lateral sclerosis."; RL Amyotroph. Lateral Scler. Frontotemporal Degener. 23:634-637(2022). CC -!- FUNCTION: Component of the serine palmitoyltransferase multisubunit CC enzyme (SPT) that catalyzes the initial and rate-limiting step in CC sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA CC (most commonly palmitoyl-CoA) to form long-chain bases. The SPT complex CC is also composed of SPTLC2 or SPTLC3 and SPTSSA or SPTSSB. Within this CC complex, the heterodimer with SPTLC2 or SPTLC3 forms the catalytic core CC (PubMed:19416851, PubMed:33558762, PubMed:36170811). The composition of CC the serine palmitoyltransferase (SPT) complex determines the substrate CC preference (PubMed:19416851, PubMed:33558762). The SPTLC1-SPTLC2-SPTSSA CC complex shows a strong preference for C16-CoA substrate, while the CC SPTLC1-SPTLC3-SPTSSA isozyme uses both C14-CoA and C16-CoA as CC substrates, with a slight preference for C14-CoA (PubMed:19416851, CC PubMed:19648650). The SPTLC1-SPTLC2-SPTSSB complex shows a strong CC preference for C18-CoA substrate, while the SPTLC1-SPTLC3-SPTSSB CC isozyme displays an ability to use a broader range of acyl-CoAs, CC without apparent preference (PubMed:19416851, PubMed:19648650, CC PubMed:33558761, PubMed:33558762). Required for adipocyte cell CC viability and metabolic homeostasis (By similarity). CC {ECO:0000250|UniProtKB:O35704, ECO:0000269|PubMed:19416851, CC ECO:0000269|PubMed:19648650, ECO:0000269|PubMed:33558761, CC ECO:0000269|PubMed:33558762, ECO:0000269|PubMed:36170811}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-serine + hexadecanoyl-CoA + H(+) = 3-oxosphinganine + CO2 + CC CoA; Xref=Rhea:RHEA:14761, ChEBI:CHEBI:15378, ChEBI:CHEBI:16526, CC ChEBI:CHEBI:33384, ChEBI:CHEBI:57287, ChEBI:CHEBI:57379, CC ChEBI:CHEBI:58299; EC=2.3.1.50; CC Evidence={ECO:0000269|PubMed:19416851}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:14762; CC Evidence={ECO:0000269|PubMed:19416851}; CC -!- CATALYTIC ACTIVITY: CC Reaction=octadecanoyl-CoA + L-serine + H(+) = 3-oxoeicosasphinganine + CC CO2 + CoA; Xref=Rhea:RHEA:33683, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:16526, ChEBI:CHEBI:33384, ChEBI:CHEBI:57287, CC ChEBI:CHEBI:57394, ChEBI:CHEBI:65073; CC Evidence={ECO:0000269|PubMed:19416851}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33684; CC Evidence={ECO:0000269|PubMed:19416851}; CC -!- CATALYTIC ACTIVITY: CC Reaction=tetradecanoyl-CoA + L-serine + H(+) = 3-oxohexadecasphinganine CC + CO2 + CoA; Xref=Rhea:RHEA:35675, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:16526, ChEBI:CHEBI:33384, ChEBI:CHEBI:57287, CC ChEBI:CHEBI:57385, ChEBI:CHEBI:71007; CC Evidence={ECO:0000269|PubMed:19416851}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:35676; CC Evidence={ECO:0000269|PubMed:19416851}; CC -!- CATALYTIC ACTIVITY: CC Reaction=dodecanoyl-CoA + L-serine + H(+) = 3-oxotetradecasphinganine + CC CO2 + CoA; Xref=Rhea:RHEA:35679, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:16526, ChEBI:CHEBI:33384, ChEBI:CHEBI:57287, CC ChEBI:CHEBI:57375, ChEBI:CHEBI:71008; CC Evidence={ECO:0000269|PubMed:19416851}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:35680; CC Evidence={ECO:0000269|PubMed:19416851}; CC -!- COFACTOR: CC Name=pyridoxal 5'-phosphate; Xref=ChEBI:CHEBI:597326; CC Evidence={ECO:0000250}; CC -!- ACTIVITY REGULATION: SPT complex catalytic activity is negatively CC regulated by ORMDL proteins, including ORMDL3, in the presence of CC ceramides (PubMed:37308477). This mechanism allows to maintain ceramide CC levels at sufficient concentrations for the production of complex CC sphingolipids, but which prevents the accumulation of ceramides to CC levels that trigger apoptosis (Probable). {ECO:0000269|PubMed:37308477, CC ECO:0000305}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=0.75 mM for L-serine {ECO:0000269|PubMed:20504773}; CC KM=0.3 mM for L-serine {ECO:0000269|PubMed:33558761}; CC Vmax=1350 pmol/min/mg enzyme {ECO:0000269|PubMed:20504773}; CC -!- PATHWAY: Lipid metabolism; sphingolipid metabolism. CC {ECO:0000269|PubMed:19416851}. CC -!- SUBUNIT: Component of the serine palmitoyltransferase (SPT) complex, CC which is also composed of SPTLC2 or SPTLC3 and SPTSSA or SPTSSB CC (PubMed:19132419, PubMed:19416851, PubMed:33558761, PubMed:33558762, CC PubMed:37308477). The heterodimer consisting of SPTLC1 and CC SPTLC2/SPTLC3 forms the catalytic core of the enzyme, while SPTSSA or CC SPTSSB subunits determine substrate specificity (PubMed:33558762, CC PubMed:37308477). SPT also interacts with ORMDL proteins, especially CC ORMDL3, which negatively regulate SPT activity in the presence of CC ceramides (PubMed:20182505, PubMed:30700557, PubMed:33558762, CC PubMed:34059824, PubMed:37308477). Forms dimers of heterodimers with CC SPTLC2 (PubMed:33558761, PubMed:33558762). Interacts with RTN4 (isoform CC B) (By similarity). {ECO:0000250|UniProtKB:O35704, CC ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:19416851, CC ECO:0000269|PubMed:20182505, ECO:0000269|PubMed:30700557, CC ECO:0000269|PubMed:33558761, ECO:0000269|PubMed:33558762, CC ECO:0000269|PubMed:34059824, ECO:0000269|PubMed:37308477}. CC -!- INTERACTION: CC O15269; Q8N138: ORMDL3; NbExp=6; IntAct=EBI-1044323, EBI-721750; CC O15269; O15270: SPTLC2; NbExp=5; IntAct=EBI-1044323, EBI-766136; CC O15269; Q9NUV7: SPTLC3; NbExp=3; IntAct=EBI-1044323, EBI-11614219; CC O15269; Q969W0: SPTSSA; NbExp=3; IntAct=EBI-1044323, EBI-723396; CC O15269-2; Q86SG2: ANKRD23; NbExp=3; IntAct=EBI-25912901, EBI-5661893; CC O15269-2; Q6ZR37: PLEKHG7; NbExp=3; IntAct=EBI-25912901, EBI-12891828; CC O15269-2; Q8IYM2: SLFN12; NbExp=3; IntAct=EBI-25912901, EBI-2822550; CC O15269-2; Q8WXH5: SOCS4; NbExp=3; IntAct=EBI-25912901, EBI-3942425; CC O15269-2; Q9UNE7: STUB1; NbExp=3; IntAct=EBI-25912901, EBI-357085; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:21618344}; Single-pass membrane protein CC {ECO:0000250|UniProtKB:O35704}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=O15269-1; Sequence=Displayed; CC Name=2; CC IsoId=O15269-2; Sequence=VSP_043127, VSP_043128; CC -!- TISSUE SPECIFICITY: Widely expressed. Not detected in small intestine. CC {ECO:0000269|PubMed:17023427}. CC -!- INDUCTION: Expression at protein level is highly increased in brains of CC patients with Alzheimer disease. No changes are observed at mRNA level. CC {ECO:0000269|PubMed:21994399}. CC -!- DOMAIN: The transmembrane domain is involved in the interaction with CC ORMDL3. {ECO:0000269|PubMed:33558762}. CC -!- PTM: Phosphorylation at Tyr-164 inhibits activity and promotes cell CC survival. {ECO:0000269|PubMed:23629659}. CC -!- DISEASE: Amyotrophic lateral sclerosis 27, juvenile (ALS27) CC [MIM:620285]: A form of amyotrophic lateral sclerosis, a CC neurodegenerative disorder affecting upper motor neurons in the brain CC and lower motor neurons in the brain stem and spinal cord, resulting in CC fatal paralysis. Sensory abnormalities are absent. The pathologic CC hallmarks of the disease include pallor of the corticospinal tract due CC to loss of motor neurons, presence of ubiquitin-positive inclusions CC within surviving motor neurons, and deposition of pathologic CC aggregates. The etiology of amyotrophic lateral sclerosis is likely to CC be multifactorial, involving both genetic and environmental factors. CC The disease is inherited in 5-10% of the cases. ALS27 is an autosomal CC dominant form manifesting as toe walking and gait abnormalities in CC early childhood. {ECO:0000269|PubMed:34059824, CC ECO:0000269|PubMed:34459874, ECO:0000269|PubMed:36204986, CC ECO:0000269|PubMed:37308477}. Note=The disease is caused by variants CC affecting the gene represented in this entry. Variants associated with CC ALS27 tend to disrupt the normal homeostatic regulation of serine CC palmitoyltransferase (SPT) by ORMDL proteins, resulting in up-regulated CC SPT activity and elevated levels of canonical SPT products. CC {ECO:0000269|PubMed:34059824}. CC -!- DISEASE: Neuropathy, hereditary sensory and autonomic, 1A (HSAN1A) CC [MIM:162400]: A form of hereditary sensory and autonomic neuropathy, a CC genetically and clinically heterogeneous group of disorders CC characterized by degeneration of dorsal root and autonomic ganglion CC cells, and by prominent sensory abnormalities with a variable degree of CC motor and autonomic dysfunction. The neurological phenotype is often CC complicated by severe infections, osteomyelitis, and amputations. CC HSAN1A is an autosomal dominant axonal form with onset in the second or CC third decades. Initial symptoms are loss of pain, touch, heat, and cold CC sensation over the feet, followed by distal muscle wasting and CC weakness. Loss of pain sensation leads to chronic skin ulcers and CC distal amputations. {ECO:0000269|PubMed:11242114, CC ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:19651702, CC ECO:0000269|PubMed:20504773, ECO:0000269|PubMed:21618344, CC ECO:0000269|PubMed:22302274, ECO:0000269|PubMed:23454272, CC ECO:0000269|PubMed:24247255, ECO:0000269|PubMed:30420926}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. Variants associated with HSAN1A tend to increase serine CC palmitoyltransferase (SPT) usage of alanine or glycine rather than CC serine, resulting in deoxysphingolipid synthesis. Deoxysphingolipids CC cannot be efficiently degraded by the cell machinery and cause cell CC toxicity. {ECO:0000305|PubMed:34059824}. CC -!- SIMILARITY: Belongs to the class-II pyridoxal-phosphate-dependent CC aminotransferase family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; Y08685; CAA69941.1; -; mRNA. DR EMBL; AF286717; AAK29328.1; -; Genomic_DNA. DR EMBL; AF286703; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286704; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286705; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286706; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286707; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286708; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286709; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286710; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286711; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286712; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286713; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286714; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286715; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286716; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AK291546; BAF84235.1; -; mRNA. DR EMBL; AL391219; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL354751; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471089; EAW62804.1; -; Genomic_DNA. DR EMBL; BC007085; AAH07085.1; -; mRNA. DR CCDS; CCDS6692.1; -. [O15269-1] DR CCDS; CCDS6693.1; -. [O15269-2] DR RefSeq; NP_001268232.1; NM_001281303.1. DR RefSeq; NP_006406.1; NM_006415.4. [O15269-1] DR RefSeq; NP_847894.1; NM_178324.3. [O15269-2] DR PDB; 6M4N; EM; 3.80 A; A/E=1-473. DR PDB; 6M4O; EM; 3.40 A; B/S=1-473. DR PDB; 7CQI; EM; 3.20 A; C/S=1-473. DR PDB; 7CQK; EM; 3.30 A; C/S=1-473. DR PDB; 7K0I; EM; 3.30 A; A/D=1-473. DR PDB; 7K0J; EM; 3.10 A; A=1-473. DR PDB; 7K0K; EM; 2.60 A; A=1-473. DR PDB; 7K0L; EM; 3.40 A; A=1-473. DR PDB; 7K0M; EM; 2.90 A; A/E=1-473. DR PDB; 7K0N; EM; 3.10 A; A/E=1-473. DR PDB; 7K0O; EM; 3.10 A; A/E=1-473. DR PDB; 7K0P; EM; 3.10 A; A/E=1-473. DR PDB; 7K0Q; EM; 3.30 A; A=1-473. DR PDB; 7YIU; EM; 2.90 A; A/E=1-473. DR PDB; 7YIY; EM; 2.70 A; A/E=1-473. DR PDB; 7YJ1; EM; 3.10 A; A/E=1-473. DR PDB; 7YJ2; EM; 2.90 A; A/E=1-473. DR PDBsum; 6M4N; -. DR PDBsum; 6M4O; -. DR PDBsum; 7CQI; -. DR PDBsum; 7CQK; -. DR PDBsum; 7K0I; -. DR PDBsum; 7K0J; -. DR PDBsum; 7K0K; -. DR PDBsum; 7K0L; -. DR PDBsum; 7K0M; -. DR PDBsum; 7K0N; -. DR PDBsum; 7K0O; -. DR PDBsum; 7K0P; -. DR PDBsum; 7K0Q; -. DR PDBsum; 7YIU; -. DR PDBsum; 7YIY; -. DR PDBsum; 7YJ1; -. DR PDBsum; 7YJ2; -. DR AlphaFoldDB; O15269; -. DR EMDB; EMD-22598; -. DR EMDB; EMD-22599; -. DR EMDB; EMD-22600; -. DR EMDB; EMD-22601; -. DR EMDB; EMD-22602; -. DR EMDB; EMD-22604; -. DR EMDB; EMD-22605; -. DR EMDB; EMD-22606; -. DR EMDB; EMD-22608; -. DR EMDB; EMD-30079; -. DR EMDB; EMD-30080; -. DR EMDB; EMD-30081; -. DR EMDB; EMD-30082; -. DR EMDB; EMD-30441; -. DR EMDB; EMD-30442; -. DR EMDB; EMD-33864; -. DR EMDB; EMD-33866; -. DR EMDB; EMD-33868; -. DR EMDB; EMD-33869; -. DR SMR; O15269; -. DR BioGRID; 115809; 198. DR ComplexPortal; CPX-6663; Serine palmitoyltransferase complex, SPTLC1-SPTLC2-SPTSSA variant. DR ComplexPortal; CPX-6664; Serine palmitoyltransferase complex, SPTLC1-SPTLC2-SPTSSB variant. DR ComplexPortal; CPX-6665; Serine palmitoyltransferase complex, SPTLC1-SPTLC3-SPTSSA variant. DR ComplexPortal; CPX-6681; Serine palmitoyltransferase complex, SPTLC1-SPTLC3-SPTSSB variant. DR CORUM; O15269; -. DR DIP; DIP-45626N; -. DR FunCoup; O15269; 3163. DR IntAct; O15269; 137. DR MINT; O15269; -. DR STRING; 9606.ENSP00000262554; -. DR BindingDB; O15269; -. DR ChEMBL; CHEMBL1250343; -. DR DrugBank; DB00114; Pyridoxal phosphate. DR DrugBank; DB00133; Serine. DR GlyGen; O15269; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; O15269; -. DR MetOSite; O15269; -. DR PhosphoSitePlus; O15269; -. DR SwissPalm; O15269; -. DR BioMuta; SPTLC1; -. DR jPOST; O15269; -. DR MassIVE; O15269; -. DR PaxDb; 9606-ENSP00000262554; -. DR PeptideAtlas; O15269; -. DR ProteomicsDB; 48557; -. [O15269-1] DR ProteomicsDB; 48558; -. [O15269-2] DR Pumba; O15269; -. DR Antibodypedia; 2269; 395 antibodies from 37 providers. DR DNASU; 10558; -. DR Ensembl; ENST00000262554.7; ENSP00000262554.2; ENSG00000090054.17. [O15269-1] DR Ensembl; ENST00000337841.4; ENSP00000337635.4; ENSG00000090054.17. [O15269-2] DR Ensembl; ENST00000690139.1; ENSP00000510483.1; ENSG00000090054.17. [O15269-2] DR GeneID; 10558; -. DR KEGG; hsa:10558; -. DR MANE-Select; ENST00000262554.7; ENSP00000262554.2; NM_006415.4; NP_006406.1. DR UCSC; uc004arl.3; human. [O15269-1] DR AGR; HGNC:11277; -. DR ClinPGx; PA36106; -. DR CTD; 10558; -. DR DisGeNET; 10558; -. DR GeneCards; SPTLC1; -. DR GeneReviews; SPTLC1; -. DR HGNC; HGNC:11277; SPTLC1. DR HPA; ENSG00000090054; Low tissue specificity. DR MalaCards; SPTLC1; -. DR MIM; 162400; phenotype. DR MIM; 605712; gene. DR MIM; 620285; phenotype. DR OpenTargets; ENSG00000090054; -. DR Orphanet; 36386; Hereditary sensory and autonomic neuropathy type 1. DR Orphanet; 300605; Juvenile amyotrophic lateral sclerosis. DR VEuPathDB; HostDB:ENSG00000090054; -. DR eggNOG; KOG1358; Eukaryota. DR GeneTree; ENSGT00550000074872; -. DR HOGENOM; CLU_015846_0_1_1; -. DR InParanoid; O15269; -. DR OMA; LTKYGCG; -. DR OrthoDB; 3168162at2759; -. DR PAN-GO; O15269; 4 GO annotations based on evolutionary models. DR PhylomeDB; O15269; -. DR BioCyc; MetaCyc:HS01673-MONOMER; -. DR BRENDA; 2.3.1.50; 2681. DR PathwayCommons; O15269; -. DR Reactome; R-HSA-1660661; Sphingolipid de novo biosynthesis. DR SABIO-RK; O15269; -. DR SignaLink; O15269; -. DR SIGNOR; O15269; -. DR UniPathway; UPA00222; -. DR Agora; ENSG00000090054; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 10558; 265 hits in 1179 CRISPR screens. DR ChiTaRS; SPTLC1; human. DR GeneWiki; SPTLC1; -. DR GenomeRNAi; 10558; -. DR Pharos; O15269; Tchem. DR PRO; PR:O15269; -. DR Proteomes; UP000005640; Chromosome 9. DR RNAct; O15269; protein. DR Bgee; ENSG00000090054; Expressed in esophagus squamous epithelium and 210 other cell types or tissues. DR ExpressionAtlas; O15269; baseline and differential. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HPA. DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome. DR GO; GO:0017059; C:serine palmitoyltransferase complex; IDA:UniProtKB. DR GO; GO:0030170; F:pyridoxal phosphate binding; IEA:InterPro. DR GO; GO:0004758; F:serine C-palmitoyltransferase activity; IDA:UniProtKB. DR GO; GO:0046513; P:ceramide biosynthetic process; IDA:MGI. DR GO; GO:1904504; P:positive regulation of lipophagy; IDA:MGI. DR GO; GO:1904649; P:regulation of fat cell apoptotic process; ISS:UniProtKB. DR GO; GO:0046511; P:sphinganine biosynthetic process; IEA:Ensembl. DR GO; GO:0030148; P:sphingolipid biosynthetic process; IDA:MGI. DR GO; GO:0006665; P:sphingolipid metabolic process; TAS:ProtInc. DR GO; GO:0006686; P:sphingomyelin biosynthetic process; IEA:Ensembl. DR GO; GO:0046512; P:sphingosine biosynthetic process; IDA:ComplexPortal. DR FunFam; 3.40.640.10:FF:000049; serine palmitoyltransferase 1 isoform X1; 1. DR Gene3D; 3.90.1150.10; Aspartate Aminotransferase, domain 1; 1. DR Gene3D; 3.40.640.10; Type I PLP-dependent aspartate aminotransferase-like (Major domain); 1. DR InterPro; IPR004839; Aminotransferase_I/II_large. DR InterPro; IPR050087; AON_synthase_class-II. DR InterPro; IPR015424; PyrdxlP-dep_Trfase. DR InterPro; IPR015421; PyrdxlP-dep_Trfase_major. DR InterPro; IPR015422; PyrdxlP-dep_Trfase_small. DR PANTHER; PTHR13693; CLASS II AMINOTRANSFERASE/8-AMINO-7-OXONONANOATE SYNTHASE; 1. DR PANTHER; PTHR13693:SF2; SERINE PALMITOYLTRANSFERASE 1; 1. DR Pfam; PF00155; Aminotran_1_2; 1. DR SUPFAM; SSF53383; PLP-dependent transferases; 1. PE 1: Evidence at protein level; KW 3D-structure; Acyltransferase; Alternative splicing; KW Amyotrophic lateral sclerosis; Disease variant; Endoplasmic reticulum; KW Lipid metabolism; Membrane; Neurodegeneration; Neuropathy; Phosphoprotein; KW Proteomics identification; Pyridoxal phosphate; Reference proteome; KW Sphingolipid metabolism; Transferase; Transmembrane; Transmembrane helix. FT CHAIN 1..473 FT /note="Serine palmitoyltransferase 1" FT /id="PRO_0000163853" FT TOPO_DOM 1..15 FT /note="Lumenal" FT /evidence="ECO:0000255" FT TRANSMEM 16..36 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 37..473 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 1..66 FT /note="Interaction with SPTLC2" FT /evidence="ECO:0000269|PubMed:33558762" FT MOD_RES 164 FT /note="Phosphotyrosine; by ABL" FT /evidence="ECO:0000269|PubMed:23629659" FT VAR_SEQ 143 FT /note="D -> E (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_043127" FT VAR_SEQ 144..473 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_043128" FT VARIANT 20 FT /note="A -> S (in ALS27; the underlying nucleotide FT substitution predominantly results in exon 2 skipping; in FT patient's whole blood sample, only exon 2 deletion was FT observed, but not the missense variant per se; when exon 2 FT deletion variant is expressed in induced pluripotent stem FT cells (iPSC) differentiated into motor neuron-like cells, FT increased production of sphinganine and ceramides is FT observed; when exon 2 deletion variant is transfected into FT HEK293 cells, decreased response to inhibition mediated by FT ORMDL3 or ceramide is observed; dbSNP:rs879254294)" FT /evidence="ECO:0000269|PubMed:34059824, FT ECO:0000269|PubMed:34459874" FT /id="VAR_088446" FT VARIANT 23 FT /note="Y -> F (in ALS27; increased production of FT sphinganine and ceramides, when expressed in induced FT pluripotent stem cells (iPSC) differentiated into motor FT neuron-like cells; decreased response to inhibition FT mediated by ORMDL3 and ceramide; no effect on the FT interaction with ORMDL3; dbSNP:rs1554716504)" FT /evidence="ECO:0000269|PubMed:34059824, FT ECO:0000269|PubMed:37308477" FT /id="VAR_088447" FT VARIANT 38 FT /note="L -> R (in ALS27; uncertain significance)" FT /evidence="ECO:0000269|PubMed:36204986" FT /id="VAR_088448" FT VARIANT 39 FT /note="Missing (in ALS27; increased production of FT sphinganine and ceramides, when expressed in induced FT pluripotent stem cells (iPSC) differentiated into motor FT neuron-like cells; decreased response to inhibition FT mediated by ORMDL3 and ceramide; no effect on the FT interaction with ORMDL3; dbSNP:rs1197928094)" FT /evidence="ECO:0000269|PubMed:34059824, FT ECO:0000269|PubMed:34459874" FT /id="VAR_088449" FT VARIANT 40..41 FT /note="Missing (in ALS27; increased production of FT sphinganine and ceramides, when expressed in induced FT pluripotent stem cells (iPSC) differentiated into motor FT neuron-like cells; decreased response to inhibition FT mediated by ORMDL3 and ceramide; no effect on the FT interaction with ORMDL3)" FT /evidence="ECO:0000269|PubMed:34059824" FT /id="VAR_088450" FT VARIANT 133 FT /note="C -> W (in HSAN1A; inactive in the heterodimeric SPT FT complex; largely reduced canonical activity towards serine; FT contrary to wild-type, uses alanine as substrate leading to FT the formation of 1-deoxysphinganine (1-deoxySa); does not FT affect the interaction with SPTLC2; dbSNP:rs119482082)" FT /evidence="ECO:0000269|PubMed:11242114, FT ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:20504773, FT ECO:0000269|PubMed:21618344, ECO:0000269|PubMed:22302274" FT /id="VAR_011392" FT VARIANT 133 FT /note="C -> Y (in HSAN1A; reduced canonical activity FT towards serine; does not affect the interaction with FT SPTLC2; dbSNP:rs119482081)" FT /evidence="ECO:0000269|PubMed:11242114, FT ECO:0000269|PubMed:19132419" FT /id="VAR_011393" FT VARIANT 144 FT /note="V -> D (in HSAN1A; reduced canonical activity FT towards serine; does not affect the interaction with FT SPTLC2; dbSNP:rs119482083)" FT /evidence="ECO:0000269|PubMed:11242114, FT ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:30420926" FT /id="VAR_011394" FT VARIANT 151 FT /note="R -> L (in dbSNP:rs45461899)" FT /evidence="ECO:0000269|PubMed:17060578" FT /id="VAR_037889" FT VARIANT 239 FT /note="R -> W (in a breast cancer sample; somatic mutation; FT dbSNP:rs542876370)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036610" FT VARIANT 310 FT /note="A -> G (found in a patient with HSAN1A; uncertain FT significance; dbSNP:rs768841574)" FT /evidence="ECO:0000269|PubMed:22302274" FT /id="VAR_068476" FT VARIANT 331 FT /note="S -> F (in HSAN1A; severe form with early onset; FT reduced canonical activity towards serine and increased FT production of deoxysphingolipids; no effect on subcellular FT location at the endoplasmic reticulum; dbSNP:rs267607087)" FT /evidence="ECO:0000269|PubMed:19651702, FT ECO:0000269|PubMed:21618344, ECO:0000269|PubMed:24247255" FT /id="VAR_066245" FT VARIANT 331 FT /note="S -> Y (in ALS27 and HSAN1A; reduced canonical FT activity towards serine and increased production of FT deoxysphingolipids; dbSNP:rs267607087)" FT /evidence="ECO:0000269|PubMed:23454272, FT ECO:0000269|PubMed:34459874" FT /id="VAR_073294" FT VARIANT 352 FT /note="A -> V (in HSAN1A; reduced canonical activity FT towards serine and increased production of FT deoxysphingolipids; no effect on subcellular location at FT the endoplasmic reticulum; dbSNP:rs267607088)" FT /evidence="ECO:0000269|PubMed:19651702, FT ECO:0000269|PubMed:21618344" FT /id="VAR_066246" FT VARIANT 387 FT /note="G -> A (does not affect catalytic activity towards FT serine; does not affect the interaction with SPTLC2; FT dbSNP:rs119482084)" FT /evidence="ECO:0000269|PubMed:15037712, FT ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:19651702" FT /id="VAR_037890" FT MUTAGEN 138 FT /note="F->A: Decreased catalytic activity with L-serine and FT palmitoyl-CoA as substrates." FT /evidence="ECO:0000269|PubMed:33558762" FT MUTAGEN 164 FT /note="Y->F: Increased serine palmitoyltransferase activity FT and sphingolipid content." FT /evidence="ECO:0000269|PubMed:23629659" FT MUTAGEN 337 FT /note="F->A: Strongly decreased catalytic activity with L- FT serine and palmitoyl-CoA as substrates." FT /evidence="ECO:0000269|PubMed:33558762" FT MUTAGEN 338 FT /note="S->A: Decreased catalytic activity with L-serine and FT palmitoyl-CoA as substrates." FT /evidence="ECO:0000269|PubMed:33558762" FT HELIX 11..18 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 22..39 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 54..63 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 78..80 FT /evidence="ECO:0007829|PDB:7K0J" FT STRAND 85..87 FT /evidence="ECO:0007829|PDB:7YJ2" FT STRAND 90..97 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 99..103 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 108..110 FT /evidence="ECO:0007829|PDB:7K0J" FT HELIX 115..128 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 136..139 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 143..156 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 159..166 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 169..178 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 184..188 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 193..201 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 205..209 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 214..229 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 232..235 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 240..247 FT /evidence="ECO:0007829|PDB:7YIY" FT TURN 249..251 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 258..267 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 270..274 FT /evidence="ECO:0007829|PDB:7YIY" FT TURN 276..281 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 282..286 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 289..293 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 297..299 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 303..306 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 309..311 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 316..320 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 322..325 FT /evidence="ECO:0007829|PDB:7YIY" FT TURN 326..331 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 333..336 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 343..358 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 362..376 FT /evidence="ECO:0007829|PDB:7YIY" FT TURN 377..379 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 383..387 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 395..400 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 405..419 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 420..422 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 433..435 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 436..438 FT /evidence="ECO:0007829|PDB:6M4O" FT STRAND 443..445 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 450..452 FT /evidence="ECO:0007829|PDB:7YIU" FT HELIX 454..468 FT /evidence="ECO:0007829|PDB:7YIY" FT TURN 469..471 FT /evidence="ECO:0007829|PDB:7YIY" SQ SEQUENCE 473 AA; 52744 MW; BA9E056A869D2EA2 CRC64; MATATEQWVL VEMVQALYEA PAYHLILEGI LILWIIRLLF SKTYKLQERS DLTVKEKEEL IEEWQPEPLV PPVPKDHPAL NYNIVSGPPS HKTVVNGKEC INFASFNFLG LLDNPRVKAA ALASLKKYGV GTCGPRGFYG TFDVHLDLED RLAKFMKTEE AIIYSYGFAT IASAIPAYSK RGDIVFVDRA ACFAIQKGLQ ASRSDIKLFK HNDMADLERL LKEQEIEDQK NPRKARVTRR FIVVEGLYMN TGTICPLPEL VKLKYKYKAR IFLEESLSFG VLGEHGRGVT EHYGINIDDI DLISANMENA LASIGGFCCG RSFVIDHQRL SGQGYCFSAS LPPLLAAAAI EALNIMEENP GIFAVLKEKC GQIHKALQGI SGLKVVGESL SPAFHLQLEE STGSREQDVR LLQEIVDQCM NRSIALTQAR YLEKEEKCLP PPSIRVVVTV EQTEEELERA ASTIKEVAQA VLL // ID TTC3_HUMAN Reviewed; 2025 AA. AC P53804; A8K7H7; B2RPA7; D3DSG9; D3DSH2; D3DSH3; O60767; P78476; P78477; AC Q569I2; Q6P578; Q9UEK4; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 30-NOV-2010, sequence version 2. DT 28-JAN-2026, entry version 215. DE RecName: Full=E3 ubiquitin-protein ligase TTC3; DE EC=2.3.2.27 {ECO:0000269|PubMed:20059950, ECO:0000269|PubMed:30696809}; DE AltName: Full=Protein DCRR1; DE AltName: Full=RING finger protein 105; DE AltName: Full=RING-type E3 ubiquitin transferase TTC3 {ECO:0000305}; DE AltName: Full=TPR repeat protein D; DE AltName: Full=Tetratricopeptide repeat protein 3; DE Short=TPR repeat protein 3; GN Name=TTC3; Synonyms=DCRR1, RNF105, TPRD; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM TPRDI), AND VARIANT HIS-1751. RC TISSUE=Brain; RX PubMed=8724848; DOI=10.1093/dnares/3.1.9; RA Ohira M., Ootsuyama A., Suzuki E., Ichikawa H., Seki N., Nagase T., RA Nomura N., Ohki M.; RT "Identification of a novel human gene containing the tetratricopeptide RT repeat domain from the Down syndrome region of chromosome 21."; RL DNA Res. 3:9-16(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS TPRDI; TPRDII AND TPRDIII), AND RP VARIANT HIS-1751. RC TISSUE=Fetal brain, and Placenta; RX PubMed=8947847; DOI=10.1093/oxfordjournals.jbchem.a021485; RA Tsukahara F., Hattori M., Muraki T., Sakaki Y.; RT "Identification and cloning of a novel cDNA belonging to tetratricopeptide RT repeat gene family from Down syndrome-critical region 21q22.2."; RL J. Biochem. 120:820-827(1996). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=10830953; DOI=10.1038/35012518; RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S., RA Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M., RA Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A., Menzel U., RA Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A., RA Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J., RA Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K., RA Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G., RA Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J., RA Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S., RA Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K., RA Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L.; RT "The DNA sequence of human chromosome 21."; RL Nature 405:311-319(2000). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM TPRDI). RC TISSUE=Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-627 (ISOFORM TPRDI). RC TISSUE=Small intestine; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 85-2025 (ISOFORM TPRDI), AND VARIANT THR-840. RX PubMed=9254009; DOI=10.3109/10425179709034031; RA Eki T., Abe M., Naitou M., Sasanuma S.I., Nohata J., Kawashima K., RA Ahmad I., Hanaoka F., Murakami Y.; RT "Cloning and characterization of novel gene, DCRR1, expressed from Down's RT syndrome critical region of human chromosome 21q22.2."; RL DNA Seq. 7:153-164(1997). RN [8] RP NUCLEOTIDE SEQUENCE [MRNA] OF 121-616 (ISOFORM TPRDI). RC TISSUE=Fetal brain; RX PubMed=9503011; DOI=10.1006/geno.1997.5146; RA Dahmane N., Ait-Ghezala G., Gosset P., Chamoun Z., Dufresne-Zacharia M.-C., RA Lopes C., Rabatel N., Gassanova-Maugenre S., Chettouh Z., Abramowski V., RA Fayet E., Yaspo M.-L., Korn B., Blouin J.-L., Lehrach H., Poustka A., RA Antonarakis S.E., Sinet P.-M., Creau N., Delabar J.-M.; RT "Transcriptional map of the 2.5-Mb CBR-ERG region of chromosome 21 involved RT in Down syndrome."; RL Genomics 48:12-23(1998). RN [9] RP FUNCTION, AND INTERACTION WITH CIT. RX PubMed=17488780; DOI=10.1242/jcs.000703; RA Berto G., Camera P., Fusco C., Imarisio S., Ambrogio C., Chiarle R., RA Silengo L., Di Cunto F.; RT "The Down syndrome critical region protein TTC3 inhibits neuronal RT differentiation via RhoA and Citron kinase."; RL J. Cell Sci. 120:1859-1867(2007). RN [10] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, SUBCELLULAR LOCATION, INTERACTION RP WITH AKT1; AKT2 AND AKT3, PHOSPHORYLATION AT SER-378, AND MUTAGENESIS OF RP SER-378. RX PubMed=20059950; DOI=10.1016/j.devcel.2009.09.007; RA Suizu F., Hiramuki Y., Okumura F., Matsuda M., Okumura A.J., Hirata N., RA Narita M., Kohno T., Yokota J., Bohgaki M., Obuse C., Hatakeyama S., RA Obata T., Noguchi M.; RT "The E3 ligase TTC3 facilitates ubiquitination and degradation of RT phosphorylated Akt."; RL Dev. Cell 17:800-810(2009). RN [11] RP FUNCTION. RX PubMed=24695496; DOI=10.1371/journal.pone.0093721; RA Berto G.E., Iobbi C., Camera P., Scarpa E., Iampietro C., Bianchi F., RA Gai M., Sgro F., Cristofani F., Gaertner A., Dotti C.G., Di Cunto F.; RT "The DCR protein TTC3 affects differentiation and Golgi compactness in RT neurons through specific actin-regulating pathways."; RL PLoS ONE 9:E93721-E93721(2014). RN [12] RP INTERACTION WITH POLG AND HSP70. RX PubMed=29290964; DOI=10.18632/oncotarget.22476; RA Gong Y., Wang X., Shang X., Xiao S.P., Li W., Shang Y., Dou F.; RT "Tetratricopeptide repeat domain 3 overexpression tends to form aggregates RT and inhibit ubiquitination and degradation of DNA polymerase gamma."; RL Oncotarget 8:106475-106485(2017). RN [13] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, INTERACTION WITH SMURF2, AND RP INDUCTION BY TGFB1. RX PubMed=30696809; DOI=10.1038/s41419-019-1308-8; RA Kim J.H., Ham S., Lee Y., Suh G.Y., Lee Y.S.; RT "TTC3 contributes to TGF-beta1-induced epithelial-mesenchymal transition RT and myofibroblast differentiation, potentially through SMURF2 RT ubiquitylation and degradation."; RL Cell Death Dis. 10:92-92(2019). RN [14] RP FUNCTION, SUBCELLULAR LOCATION, AND PROTEOLYTIC CLEAVAGE. RX PubMed=30203323; DOI=10.1007/s12017-018-8509-7; RA Gong Y., Wang K., Xiao S.P., Mi P., Li W., Shang Y., Dou F.; RT "Overexpressed TTC3 Protein Tends to be Cleaved into Fragments and Form RT Aggregates in the Nucleus."; RL NeuroMolecular Med. 21:85-96(2019). RN [15] RP VARIANT [LARGE SCALE ANALYSIS] MET-1289. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). RN [16] RP VARIANT CYS-1038. RX PubMed=27066578; DOI=10.1212/nxg.0000000000000041; RA Kohli M.A., Cukier H.N., Hamilton-Nelson K.L., Rolati S., Kunkle B.W., RA Whitehead P.L., Zuechner S.L., Farrer L.A., Martin E.R., Beecham G.W., RA Haines J.L., Vance J.M., Cuccaro M.L., Gilbert J.R., Schellenberg G.D., RA Carney R.M., Pericak-Vance M.A.; RT "Segregation of a rare TTC3 variant in an extended family with late-onset RT Alzheimer disease."; RL Neurol. Genet. 2:E41-E41(2016). CC -!- FUNCTION: E3 ubiquitin-protein ligase which catalyzes the formation of CC 'Lys-48'-polyubiquitin chains (PubMed:20059950, PubMed:30696809). CC Mediates the ubiquitination and subsequent degradation of CC phosphorylated Akt (AKT1, AKT2 and AKT3) in the nucleus CC (PubMed:20059950). Acts as a terminal regulator of Akt signaling after CC activation; its phosphorylation by Akt, which is a prerequisite for CC ubiquitin ligase activity, suggests the existence of a regulation CC mechanism required to control Akt levels after activation CC (PubMed:20059950). Positively regulates TGFB1-induced epithelial- CC mesenchymal transition and myofibroblast differentiation by mediating CC the ubiquitination and subsequent degradation of SMURF2 CC (PubMed:30696809). Regulates neuronal differentiation by regulating CC actin remodeling and Golgi organization via a signaling cascade CC involving RHOA, CIT and ROCK (PubMed:17488780, PubMed:24695496). CC Inhibits cell proliferation (PubMed:30203323). CC {ECO:0000269|PubMed:17488780, ECO:0000269|PubMed:20059950, CC ECO:0000269|PubMed:24695496, ECO:0000269|PubMed:30203323, CC ECO:0000269|PubMed:30696809}. CC -!- CATALYTIC ACTIVITY: CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; CC EC=2.3.2.27; Evidence={ECO:0000269|PubMed:20059950, CC ECO:0000269|PubMed:30696809}; CC -!- PATHWAY: Protein modification; protein ubiquitination. CC {ECO:0000269|PubMed:20059950, ECO:0000269|PubMed:30696809}. CC -!- SUBUNIT: Interacts (when phosphorylated on Ser-378) with AKT1, AKT2 and CC AKT3 (when phosphorylated) (PubMed:20059950). Interacts with CIT CC (PubMed:17488780). Interacts with POLG (PubMed:29290964). Interacts CC with HSP70 (PubMed:29290964). Interacts with SMURF2 (PubMed:30696809). CC {ECO:0000269|PubMed:17488780, ECO:0000269|PubMed:20059950, CC ECO:0000269|PubMed:29290964, ECO:0000269|PubMed:30696809}. CC -!- INTERACTION: CC P53804; P31749: AKT1; NbExp=4; IntAct=EBI-2681313, EBI-296087; CC P53804; P31751: AKT2; NbExp=5; IntAct=EBI-2681313, EBI-296058; CC P53804; Q9Y243: AKT3; NbExp=2; IntAct=EBI-2681313, EBI-296115; CC P53804; Q9HAU4: SMURF2; NbExp=2; IntAct=EBI-2681313, EBI-396727; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:20059950, CC ECO:0000269|PubMed:30203323}. Cytoplasm {ECO:0000269|PubMed:30203323}. CC Golgi apparatus {ECO:0000250|UniProtKB:D3ZSP7}. Note=Nuclear CC localization may be dependent on the proteolytic cleavage of full CC length protein in the cytoplasm (PubMed:30203323). This cleavage may CC reveal an N-terminal nuclear localization signal, allowing N-terminal CC fragments to enter the nucleus (PubMed:30203323). CC {ECO:0000269|PubMed:30203323}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=TPRDI; CC IsoId=P53804-1; Sequence=Displayed; CC Name=TPRDII; CC IsoId=P53804-2; Sequence=VSP_006554; CC Name=TPRDIII; CC IsoId=P53804-3; Sequence=VSP_006555; CC -!- TISSUE SPECIFICITY: Found in all tissues examined. CC -!- INDUCTION: Up-regulated by TGFB1 signaling. CC {ECO:0000269|PubMed:30696809}. CC -!- PTM: Phosphorylation on Ser-378 by Akt is required for ubiquitin ligase CC activity. {ECO:0000269|PubMed:20059950}. CC -!- PTM: Proteolytically cleaved into differently sized N- and C-terminal CC fragments. {ECO:0000269|PubMed:30203323}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH63033.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; CC Sequence=AAH92466.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; D83077; BAA11769.1; -; mRNA. DR EMBL; D84294; BAA12301.1; -; mRNA. DR EMBL; D84295; BAA12302.1; -; mRNA. DR EMBL; D84296; BAA12303.1; -; mRNA. DR EMBL; AP001429; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP001432; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471079; EAX09716.1; -; Genomic_DNA. DR EMBL; CH471079; EAX09717.1; -; Genomic_DNA. DR EMBL; CH471079; EAX09718.1; -; Genomic_DNA. DR EMBL; CH471079; EAX09719.1; -; Genomic_DNA. DR EMBL; CH471079; EAX09720.1; -; Genomic_DNA. DR EMBL; CH471079; EAX09721.1; -; Genomic_DNA. DR EMBL; CH471079; EAX09722.1; -; Genomic_DNA. DR EMBL; CH471079; EAX09723.1; -; Genomic_DNA. DR EMBL; BC063033; AAH63033.1; ALT_SEQ; mRNA. DR EMBL; BC092466; AAH92466.1; ALT_SEQ; mRNA. DR EMBL; BC137345; AAI37346.1; -; mRNA. DR EMBL; AK291992; BAF84681.1; -; mRNA. DR EMBL; D83327; BAA23666.1; -; mRNA. DR EMBL; AJ001866; CAA05057.1; -; mRNA. DR CCDS; CCDS13651.1; -. [P53804-1] DR CCDS; CCDS93096.1; -. [P53804-3] DR PIR; JC5020; JC5020. DR RefSeq; NP_001001894.1; NM_001001894.3. [P53804-1] DR RefSeq; NP_001307633.1; NM_001320704.1. DR RefSeq; NP_001317610.1; NM_001330681.2. [P53804-3] DR RefSeq; NP_001317611.1; NM_001330682.2. [P53804-3] DR RefSeq; NP_001317612.1; NM_001330683.2. [P53804-1] DR RefSeq; NP_001340865.1; NM_001353936.2. [P53804-3] DR RefSeq; NP_003307.3; NM_003316.3. [P53804-1] DR AlphaFoldDB; P53804; -. DR BioGRID; 113118; 135. DR ELM; P53804; -. DR FunCoup; P53804; 3414. DR IntAct; P53804; 110. DR MINT; P53804; -. DR STRING; 9606.ENSP00000381981; -. DR GlyGen; P53804; 1 site. DR iPTMnet; P53804; -. DR PhosphoSitePlus; P53804; -. DR BioMuta; TTC3; -. DR DMDM; 313104040; -. DR jPOST; P53804; -. DR MassIVE; P53804; -. DR PaxDb; 9606-ENSP00000381981; -. DR PeptideAtlas; P53804; -. DR ProteomicsDB; 56623; -. [P53804-1] DR ProteomicsDB; 56624; -. [P53804-2] DR ProteomicsDB; 56625; -. [P53804-3] DR Pumba; P53804; -. DR Antibodypedia; 8442; 69 antibodies from 19 providers. DR DNASU; 7267; -. DR Ensembl; ENST00000354749.6; ENSP00000346791.2; ENSG00000182670.14. [P53804-1] DR Ensembl; ENST00000399017.6; ENSP00000381981.2; ENSG00000182670.14. [P53804-1] DR Ensembl; ENST00000418766.6; ENSP00000403943.2; ENSG00000182670.14. [P53804-1] DR Ensembl; ENST00000450533.6; ENSP00000408456.2; ENSG00000182670.14. [P53804-1] DR Ensembl; ENST00000463216.6; ENSP00000512893.1; ENSG00000182670.14. [P53804-3] DR Ensembl; ENST00000492275.6; ENSP00000512889.1; ENSG00000182670.14. [P53804-3] DR GeneID; 7267; -. DR KEGG; hsa:7267; -. DR MANE-Select; ENST00000418766.6; ENSP00000403943.2; NM_001330683.2; NP_001317612.1. DR UCSC; uc002yvz.4; human. [P53804-1] DR AGR; HGNC:12393; -. DR ClinPGx; PA37058; -. DR CTD; 7267; -. DR DisGeNET; 7267; -. DR GeneCards; TTC3; -. DR HGNC; HGNC:12393; TTC3. DR HPA; ENSG00000182670; Low tissue specificity. DR MIM; 602259; gene. DR OpenTargets; ENSG00000182670; -. DR VEuPathDB; HostDB:ENSG00000182670; -. DR eggNOG; KOG0800; Eukaryota. DR GeneTree; ENSGT00940000154465; -. DR HOGENOM; CLU_001829_1_0_1; -. DR InParanoid; P53804; -. DR OMA; CEDVRAK; -. DR OrthoDB; 8062037at2759; -. DR PAN-GO; P53804; 2 GO annotations based on evolutionary models. DR PhylomeDB; P53804; -. DR PathwayCommons; P53804; -. DR SignaLink; P53804; -. DR SIGNOR; P53804; -. DR UniPathway; UPA00143; -. DR Agora; ENSG00000182670; -. DR BioGRID-ORCS; 7267; 10 hits in 1195 CRISPR screens. DR ChiTaRS; TTC3; human. DR GeneWiki; TTC3; -. DR GenomeRNAi; 7267; -. DR Pharos; P53804; Tbio. DR PRO; PR:P53804; -. DR Proteomes; UP000005640; Chromosome 21. DR RNAct; P53804; protein. DR Bgee; ENSG00000182670; Expressed in cortical plate and 210 other cell types or tissues. DR ExpressionAtlas; P53804; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell. DR GO; GO:0005730; C:nucleolus; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IEA:UniProtKB-EC. DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW. DR GO; GO:0070936; P:protein K48-linked ubiquitination; IDA:UniProtKB. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:UniProtKB. DR CDD; cd16481; RING-H2_TTC3; 1. DR FunFam; 1.25.40.10:FF:000370; E3 ubiquitin-protein ligase TTC3; 1. DR FunFam; 1.25.40.10:FF:000143; E3 ubiquitin-protein ligase TTC3 isoform X2; 1. DR FunFam; 3.30.40.10:FF:000529; Tetratricopeptide repeat domain 3; 1. DR Gene3D; 1.10.533.10; Death Domain, Fas; 1. DR Gene3D; 1.25.40.10; Tetratricopeptide repeat domain; 2. DR Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 1. DR InterPro; IPR011029; DEATH-like_dom_sf. DR InterPro; IPR011990; TPR-like_helical_dom_sf. DR InterPro; IPR019734; TPR_rpt. DR InterPro; IPR056872; TTC3/DZIP3-like_helical. DR InterPro; IPR056870; TTC3/DZIP3/RBM44-like_helical. DR InterPro; IPR043866; TTC3/DZIP3_dom. DR InterPro; IPR056871; WH_TTC3. DR InterPro; IPR001841; Znf_RING. DR InterPro; IPR013083; Znf_RING/FYVE/PHD. DR PANTHER; PTHR17550; E3 UBIQUITIN-PROTEIN LIGASE TTC3; 1. DR PANTHER; PTHR17550:SF6; E3 UBIQUITIN-PROTEIN LIGASE TTC3; 1. DR Pfam; PF24525; TTC3; 1. DR Pfam; PF24905; TTC3_9th; 1. DR Pfam; PF19179; TTC3_DZIP3_dom; 1. DR Pfam; PF24812; WHD_TTC3; 1. DR Pfam; PF13639; zf-RING_2; 1. DR SMART; SM00184; RING; 1. DR SMART; SM00028; TPR; 4. DR SUPFAM; SSF57850; RING/U-box; 1. DR SUPFAM; SSF48452; TPR-like; 2. DR PROSITE; PS50005; TPR; 2. DR PROSITE; PS50293; TPR_REGION; 2. DR PROSITE; PS50089; ZF_RING_2; 1. PE 1: Evidence at protein level; KW Alternative splicing; Cytoplasm; Golgi apparatus; Metal-binding; Nucleus; KW Phosphoprotein; Proteomics identification; Reference proteome; Repeat; KW TPR repeat; Transferase; Ubl conjugation pathway; Zinc; Zinc-finger. FT CHAIN 1..2025 FT /note="E3 ubiquitin-protein ligase TTC3" FT /id="PRO_0000106378" FT REPEAT 231..264 FT /note="TPR 1" FT REPEAT 266..298 FT /note="TPR 2" FT REPEAT 536..572 FT /note="TPR 3" FT REPEAT 576..609 FT /note="TPR 4" FT ZN_FING 1957..1997 FT /note="RING-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175" FT REGION 1..230 FT /note="Interaction with POLG" FT /evidence="ECO:0000269|PubMed:29290964" FT REGION 423..458 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 786..805 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1012..1068 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1215..1295 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1773..1842 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1894..1944 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 2004..2025 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 793..805 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1019..1029 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1038..1052 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1894..1912 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1913..1928 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 2013..2025 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 378 FT /note="Phosphoserine; by PKB/AKT2" FT /evidence="ECO:0000269|PubMed:20059950" FT MOD_RES 1009 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O88196" FT MOD_RES 1061 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O88196" FT VAR_SEQ 1..310 FT /note="Missing (in isoform TPRDIII)" FT /evidence="ECO:0000303|PubMed:8947847" FT /id="VSP_006555" FT VAR_SEQ 1..233 FT /note="Missing (in isoform TPRDII)" FT /evidence="ECO:0000303|PubMed:8947847" FT /id="VSP_006554" FT VARIANT 840 FT /note="M -> T (in dbSNP:rs1053808)" FT /evidence="ECO:0000269|PubMed:9254009" FT /id="VAR_020312" FT VARIANT 1038 FT /note="S -> C (in an extended family with high risk of FT late-onset Alzheimer Disease; dbSNP:rs377155188)" FT /evidence="ECO:0000269|PubMed:27066578" FT /id="VAR_082645" FT VARIANT 1154 FT /note="P -> S (in dbSNP:rs1053840)" FT /id="VAR_044428" FT VARIANT 1289 FT /note="K -> M (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_035868" FT VARIANT 1751 FT /note="D -> H (in dbSNP:rs1053966)" FT /evidence="ECO:0000269|PubMed:8724848, FT ECO:0000269|PubMed:8947847" FT /id="VAR_024676" FT MUTAGEN 378 FT /note="S->A: Abolishes phosphorylation by Akt and impairs FT ubiquitin ligase activity on Akt." FT /evidence="ECO:0000269|PubMed:20059950" FT CONFLICT 9 FT /note="F -> Y (in Ref. 5; AAH92466)" FT /evidence="ECO:0000305" FT CONFLICT 121 FT /note="N -> D (in Ref. 8; CAA05057)" FT /evidence="ECO:0000305" FT CONFLICT 139 FT /note="K -> R (in Ref. 8; CAA05057)" FT /evidence="ECO:0000305" FT CONFLICT 232 FT /note="E -> G (in Ref. 8; CAA05057)" FT /evidence="ECO:0000305" FT CONFLICT 276 FT /note="L -> P (in Ref. 8; CAA05057)" FT /evidence="ECO:0000305" FT CONFLICT 437 FT /note="K -> Q (in Ref. 5; AAH63033)" FT /evidence="ECO:0000305" FT CONFLICT 495 FT /note="Q -> P (in Ref. 7; BAA23666)" FT /evidence="ECO:0000305" FT CONFLICT 1700 FT /note="E -> V (in Ref. 7; BAA23666)" FT /evidence="ECO:0000305" FT CONFLICT 1822 FT /note="A -> T (in Ref. 7; BAA23666)" FT /evidence="ECO:0000305" SQ SEQUENCE 2025 AA; 229869 MW; C80BC8E1970B6725 CRC64; MDNFAEGDFT VADYALLEDC PHVDDCVFAA EFMSNDYVRV TQLYCDGVGV QYKDYIQSER NLEFDICSIW CSKPISVLQD YCDAIKINIF WPLLFQHQNS SVISRLHPCV DANNSRASEI NLKKLQHLEL MEDIVDLAKK VANDSFLIGG LLRIGCKIEN KILAMEEALN WIKYAGDVTI LTKLGSIDNC WPMLSIFFTE YKYHITKIVM EDCNLLEELK TQSCMDCIEE GELMKMKGNE EFSKERFDIA IIYYTRAIEY RPENYLLYGN RALCFLRTGQ FRNALGDGKR ATILKNTWPK GHYRYCDALS MLGEYDWALQ ANIKAQKLCK NDPEGIKDLI QQHVKLQKQI EDLQGRTANK DPIKAFYENR AYTPRSLSAP IFTTSLNFVE KERDFRKINH EMANGGNQNL KVADEALKVD DCDCHPEFSP PSSQPPKHKG KQKSRNNESE KFSSSSPLTL PADLKNILEK QFSKSSRAAH QDFANIMKML RSLIQDGYMA LLEQRCRSAA QAFTELLNGL DPQKIKQLNL AMINYVLVVY GLAISLLGIG QPEELSEAEN QFKRIIEHYP SEGLDCLAYC GIGKVYLKKN RFLEALNHFE KARTLIYRLP GVLTWPTSNV IIEESQPQKI KMLLEKFVEE CKFPPVPDAI CCYQKCHGYS KIQIYITDPD FKGFIRISCC QYCKIEFHMN CWKKLKTTTF NDKIDKDFLQ GICLTPDCEG VISKIIIFSS GGEVKCEFEH KVIKEKVPPR PILKQKCSSL EKLRLKEDKK LKRKIQKKEA KKLAQERMEE DLRESNPPKN EEQKETVDNV QRCQFLDDRI LQCIKQYADK IKSGIQNTAM LLKELLSWKV LSTEDYTTCF SSRNFLNEAV DYVIRHLIQE NNRVKTRIFL HVLSELKEVE PKLAAWIQKL NSFGLDATGT FFSRYGASLK LLDFSIMTFL WNEKYGHKLD SIEGKQLDYF SEPASLKEAR CLIWLLEEHR DKFPALHSAL DEFFDIMDSR CTVLRKQDSG EAPFSSTKVK NKSKKKKPKD SKPMLVGSGT TSVTSNNEII TSSEDHSNRN SDSAGPFAVP DHLRQDVEEF EALYDQHSNE YVVRNKKLWD MNPKQKCSTL YDYFSQFLEE HGPLDMSNKM FSAEYEFFPE ETRQILEKAG GLKPFLLGCP RFVVIDNCIA LKKVASRLKK KRKKKNIKTK VEEISKAGEY VRVKLQLNPA AREFKPDVKS KPVSDSSSAP AFENVKPKPV SANSPKPACE DVKAKPVSDN SSRQVSEDGQ PKGVSSNSPK PGSEDANYKR VSCNSPKPVL EDVKPTYWAQ SHLVTGYCTY LPFQRFDITQ TPPAYINVLP GLPQYTSIYT PLASLSPEYQ LPRSVPVVPS FVANDRADKN AAAYFEGHHL NAENVAGHQI ASETQILEGS LGISVKSHCS TGDAHTVLSE SNRNDEHCGN SNNKCEVIPE STSAVTNIPH VQMVAIQVSW NIIHQEVNTE PYNPFEERQG EISRIEKEHQ VLQDQLQEVY ENYEQIKLKG LEETRDLEEK LKRHLEENKI SKTELDWFLQ DLEREIKKWQ QEKKEIQERL KSLKKKIKKV SNASEMYTQK NDGKEKEHEL HLDQSLEISN TLTNEKMKIE EYIKKGKEDY EESHQRAVAA EVSVLENWKE SEVYKLQIME SQAEAFLKKL GLISRDPAAY PDMESDIRSW ELFLSNVTKE IEKAKSQFEE QIKAIKNGSR LSELSKVQIS ELSFPACNTV HPELLPESSG DDGQGLVTSA SDVTGNHAAL HRDPSVFSAG DSPGEAPSAL LPGPPPGQPE ATQLTGPKRA GQAALSERSP VADRKQPVPP GRAARSSQSP KKPFNSIIEH LSVVFPCYNS TELAGFIKKV RSKNKNSLSG LSIDEIVQRV TEHILDEQKK KKPNPGKDKR TYEPSSATPV TRSSQGSPSV VVAPSPKTKG QKAEDVPVRI ALGASSCEIC HEVFKSKNVR VLKCGHKYHK GCFKQWLKGQ SACPACQGRD LLTEESPSGR GWPSQNQELP SCSSR // ID UNC5C_HUMAN Reviewed; 931 AA. AC O95185; Q8IUT0; DT 11-OCT-2004, integrated into UniProtKB/Swiss-Prot. DT 05-MAY-2009, sequence version 2. DT 28-JAN-2026, entry version 191. DE RecName: Full=Netrin receptor UNC5C; DE AltName: Full=Protein unc-5 homolog 3; DE AltName: Full=Protein unc-5 homolog C; DE Flags: Precursor; GN Name=UNC5C; Synonyms=UNC5H3; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND VARIANT RP THR-721. RC TISSUE=Brain; RX PubMed=9782087; DOI=10.1006/geno.1998.5425; RA Ackerman S.L., Knowles B.B.; RT "Cloning and mapping of the UNC5C gene to human chromosome 4q21-q23."; RL Genomics 52:205-208(1998). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Lung; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP DOWN-REGULATION IN CANCER. RX PubMed=12655055; DOI=10.1073/pnas.0738063100; RA Thiebault K., Mazelin L., Pays L., Llambi F., Joly M.-O., Scoazec J.-Y., RA Saurin J.-C., Romeo G., Mehlen P.; RT "The netrin-1 receptors UNC5H are putative tumor suppressors controlling RT cell death commitment."; RL Proc. Natl. Acad. Sci. U.S.A. 100:4173-4178(2003). RN [5] RP INTERACTION WITH DSCAM. RX PubMed=22685302; DOI=10.1074/jbc.m112.340174; RA Purohit A.A., Li W., Qu C., Dwyer T., Shao Q., Guan K.L., Liu G.; RT "Down syndrome cell adhesion molecule (DSCAM) associates with RT uncoordinated-5C (UNC5C) in netrin-1-mediated growth cone collapse."; RL J. Biol. Chem. 287:27126-27138(2012). RN [6] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, INVOLVEMENT IN AD, VARIANT AD RP MET-835, AND CHARACTERIZATION OF VARIANT AD MET-835. RX PubMed=25419706; DOI=10.1038/nm.3736; RG Alzheimer's Disease Genetics Consortium; RA Wetzel-Smith M.K., Hunkapiller J., Bhangale T.R., Srinivasan K., RA Maloney J.A., Atwal J.K., Sa S.M., Yaylaoglu M.B., Foreman O., Ortmann W., RA Rathore N., Hansen D.V., Tessier-Lavigne M., Mayeux R., Pericak-Vance M., RA Haines J., Farrer L.A., Schellenberg G.D., Goate A., Behrens T.W., RA Cruchaga C., Watts R.J., Graham R.R.; RT "A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and RT increases neuronal cell death."; RL Nat. Med. 20:1452-1457(2014). RN [7] RP INTERACTION WITH DAPK1, AND CHARACTERIZATION OF VARIANT AD MET-835. RX PubMed=27068745; DOI=10.1074/jbc.m115.698092; RA Hashimoto Y., Toyama Y., Kusakari S., Nawa M., Matsuoka M.; RT "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor RT Uncoordinated-5C-induced Signaling That Merges with Amyloid beta Precursor RT Protein Signaling."; RL J. Biol. Chem. 291:12282-12293(2016). RN [8] RP FUNCTION, AND INTERACTION WITH TUBB3. RX PubMed=28483977; DOI=10.1523/jneurosci.2617-16.2017; RA Shao Q., Yang T., Huang H., Alarmanazi F., Liu G.; RT "Uncoupling of UNC5C with Polymerized TUBB3 in Microtubules Mediates RT Netrin-1 Repulsion."; RL J. Neurosci. 37:5620-5633(2017). CC -!- FUNCTION: Receptor for netrin required for axon guidance (By CC similarity). Mediates axon repulsion of neuronal growth cones in the CC developing nervous system upon ligand binding (By similarity). CC NTN1/Netrin-1 binding might cause dissociation of UNC5C from CC polymerized TUBB3 in microtubules and thereby lead to increased CC microtubule dynamics and axon repulsion (PubMed:28483977). Axon CC repulsion in growth cones may also be caused by its association with CC DCC that may trigger signaling for repulsion (By similarity). Might CC also collaborate with DSCAM in NTN1-mediated axon repulsion CC independently of DCC (By similarity). Also involved in corticospinal CC tract axon guidance independently of DCC (By similarity). Involved in CC dorsal root ganglion axon projection towards the spinal cord CC (PubMed:28483977). It also acts as a dependence receptor required for CC apoptosis induction when not associated with netrin ligand (By CC similarity). {ECO:0000250|UniProtKB:O08747, CC ECO:0000250|UniProtKB:Q761X5, ECO:0000269|PubMed:28483977}. CC -!- SUBUNIT: Interacts with DCC (via cytoplasmic domain) (By similarity). CC Interacts (tyrosine phosphorylated form) with PTPN11 (By similarity). CC Interacts (via extracellular domain) with FLRT3 (via extracellular CC domain) (By similarity). Interacts (via Ig-like C2-type domain) with CC DSCAM (via extracellular domain) (PubMed:22685302). Interacts (via CC death domain) with DAPK1 (PubMed:27068745). Interacts (via cytoplasmic CC domain) with TUBB3; this interaction is decreased by NTN1/Netrin-1 CC (PubMed:28483977). {ECO:0000250|UniProtKB:O08747, CC ECO:0000269|PubMed:22685302, ECO:0000269|PubMed:27068745, CC ECO:0000269|PubMed:28483977}. CC -!- INTERACTION: CC O95185; Q13509: TUBB3; NbExp=2; IntAct=EBI-11343380, EBI-350989; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:25419706}; CC Single-pass type I membrane protein {ECO:0000255}. Cell surface CC {ECO:0000269|PubMed:25419706}. Synapse, synaptosome CC {ECO:0000250|UniProtKB:Q761X5}. Cell projection, axon CC {ECO:0000250|UniProtKB:O08747}. Cell projection, dendrite CC {ECO:0000250|UniProtKB:O08747}. Cell projection, growth cone CC {ECO:0000250|UniProtKB:O08747}. Cell projection, lamellipodium CC {ECO:0000250|UniProtKB:O08747}. Cell projection, filopodium CC {ECO:0000250|UniProtKB:O08747}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=O95185-1; Sequence=Displayed; CC Name=2; CC IsoId=O95185-2; Sequence=VSP_011700, VSP_011701; CC -!- TISSUE SPECIFICITY: Mainly expressed in brain (PubMed:9782087). CC Expressed in temporal lobe cortical neurons and in neurons of the CC hippocampal pyramidal layer (PubMed:25419706). Also expressed in kidney CC (PubMed:9782087). Not expressed in developing or adult lung CC (PubMed:9782087). {ECO:0000269|PubMed:25419706, CC ECO:0000269|PubMed:9782087}. CC -!- PTM: Proteolytically cleaved by caspases during apoptosis. The cleavage CC does not take place when the receptor is associated with netrin ligand. CC Its cleavage by caspases is required to induce apoptosis. CC {ECO:0000250|UniProtKB:Q761X5}. CC -!- PTM: Phosphorylated on different cytoplasmic tyrosine residues. CC Phosphorylation of Tyr-568 leads to an interaction with PTPN11 CC phosphatase, suggesting that its activity is regulated by CC phosphorylation/dephosphorylation. Tyrosine phosphorylation is netrin- CC dependent. {ECO:0000250|UniProtKB:O08747}. CC -!- DISEASE: Alzheimer disease (AD) [MIM:104300]: Alzheimer disease is a CC neurodegenerative disorder characterized by progressive dementia, loss CC of cognitive abilities, and deposition of fibrillar amyloid proteins as CC intraneuronal neurofibrillary tangles, extracellular amyloid plaques CC and vascular amyloid deposits. The major constituents of these plaques CC are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, CC that are produced by the proteolysis of the transmembrane APP protein. CC The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved CC products, such as C31, are also implicated in neuronal death. CC {ECO:0000269|PubMed:25419706, ECO:0000269|PubMed:27068745}. CC Note=Disease susceptibility may be associated with variants affecting CC the gene represented in this entry. CC -!- MISCELLANEOUS: Down-regulated in multiple cancers including colorectal, CC breast, ovary, uterus, stomach, lung, or kidney cancers. CC {ECO:0000269|PubMed:12655055}. CC -!- SIMILARITY: Belongs to the unc-5 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF055634; AAC67491.1; -; mRNA. DR EMBL; AC098584; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC105395; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC106881; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC041156; AAH41156.1; -; mRNA. DR CCDS; CCDS3643.1; -. [O95185-1] DR RefSeq; NP_003719.3; NM_003728.3. [O95185-1] DR AlphaFoldDB; O95185; -. DR SMR; O95185; -. DR BioGRID; 114186; 38. DR DIP; DIP-46276N; -. DR FunCoup; O95185; 326. DR IntAct; O95185; 9. DR MINT; O95185; -. DR STRING; 9606.ENSP00000406022; -. DR GlyCosmos; O95185; 2 sites, No reported glycans. DR GlyGen; O95185; 3 sites, 1 O-linked glycan (1 site). DR iPTMnet; O95185; -. DR PhosphoSitePlus; O95185; -. DR BioMuta; UNC5C; -. DR jPOST; O95185; -. DR MassIVE; O95185; -. DR PaxDb; 9606-ENSP00000406022; -. DR PeptideAtlas; O95185; -. DR ProteomicsDB; 50694; -. [O95185-1] DR ProteomicsDB; 50695; -. [O95185-2] DR Pumba; O95185; -. DR Antibodypedia; 2665; 258 antibodies from 33 providers. DR DNASU; 8633; -. DR Ensembl; ENST00000453304.6; ENSP00000406022.1; ENSG00000182168.16. [O95185-1] DR Ensembl; ENST00000506749.5; ENSP00000426153.1; ENSG00000182168.16. [O95185-2] DR GeneID; 8633; -. DR KEGG; hsa:8633; -. DR MANE-Select; ENST00000453304.6; ENSP00000406022.1; NM_003728.4; NP_003719.3. DR UCSC; uc003hto.4; human. [O95185-1] DR AGR; HGNC:12569; -. DR ClinPGx; PA37206; -. DR CTD; 8633; -. DR DisGeNET; 8633; -. DR GeneCards; UNC5C; -. DR HGNC; HGNC:12569; UNC5C. DR HPA; ENSG00000182168; Tissue enhanced (thyroid). DR MalaCards; UNC5C; -. DR MIM; 104300; phenotype. DR MIM; 603610; gene. DR OpenTargets; ENSG00000182168; -. DR VEuPathDB; HostDB:ENSG00000182168; -. DR eggNOG; KOG1480; Eukaryota. DR GeneTree; ENSGT00950000182815; -. DR HOGENOM; CLU_014383_2_1_1; -. DR InParanoid; O95185; -. DR OMA; CECQAWS; -. DR OrthoDB; 5973910at2759; -. DR PAN-GO; O95185; 2 GO annotations based on evolutionary models. DR PhylomeDB; O95185; -. DR PathwayCommons; O95185; -. DR Reactome; R-HSA-418886; Netrin mediated repulsion signals. DR SignaLink; O95185; -. DR SIGNOR; O95185; -. DR Agora; ENSG00000182168; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 8633; 6 hits in 1142 CRISPR screens. DR ChiTaRS; UNC5C; human. DR GeneWiki; UNC5C; -. DR GenomeRNAi; 8633; -. DR Pharos; O95185; Tbio. DR PRO; PR:O95185; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; O95185; protein. DR Bgee; ENSG00000182168; Expressed in corpus callosum and 134 other cell types or tissues. DR ExpressionAtlas; O95185; baseline and differential. DR GO; GO:0009986; C:cell surface; IEA:UniProtKB-SubCell. DR GO; GO:0030425; C:dendrite; IEA:UniProtKB-SubCell. DR GO; GO:0030175; C:filopodium; ISS:UniProtKB. DR GO; GO:0030426; C:growth cone; ISS:UniProtKB. DR GO; GO:0030027; C:lamellipodium; ISS:UniProtKB. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0045202; C:synapse; IEA:UniProtKB-SubCell. DR GO; GO:0005042; F:netrin receptor activity; IBA:GO_Central. DR GO; GO:0005043; F:netrin receptor activity involved in chemorepulsion; ISS:UniProtKB. DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB. DR GO; GO:0015631; F:tubulin binding; IPI:UniProtKB. DR GO; GO:0033564; P:anterior/posterior axon guidance; IEA:Ensembl. DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW. DR GO; GO:0007411; P:axon guidance; IBA:GO_Central. DR GO; GO:0007420; P:brain development; TAS:ProtInc. DR GO; GO:0061643; P:chemorepulsion of axon; ISS:UniProtKB. DR GO; GO:1990791; P:dorsal root ganglion development; IDA:UniProtKB. DR GO; GO:0035234; P:ectopic germ cell programmed cell death; IEA:Ensembl. DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0051094; P:positive regulation of developmental process; IEA:Ensembl. DR GO; GO:2000243; P:positive regulation of reproductive process; IEA:Ensembl. DR GO; GO:2001222; P:regulation of neuron migration; IEA:Ensembl. DR CDD; cd08799; Death_UNC5C; 1. DR FunFam; 1.10.533.10:FF:000001; Unc-5 netrin receptor B; 1. DR FunFam; 2.20.100.10:FF:000002; Unc-5 netrin receptor C; 1. DR FunFam; 2.20.100.10:FF:000008; Unc-5 netrin receptor C; 1. DR FunFam; 2.60.220.30:FF:000003; Unc-5 netrin receptor C; 1. DR FunFam; 2.60.40.10:FF:000037; Unc-5 netrin receptor C; 1. DR FunFam; 2.60.40.10:FF:000039; Unc-5 netrin receptor C; 1. DR Gene3D; 2.60.220.30; -; 1. DR Gene3D; 1.10.533.10; Death Domain, Fas; 1. DR Gene3D; 2.60.40.10; Immunoglobulins; 2. DR Gene3D; 2.20.100.10; Thrombospondin type-1 (TSP1) repeat; 2. DR InterPro; IPR011029; DEATH-like_dom_sf. DR InterPro; IPR000488; Death_dom. DR InterPro; IPR042154; Death_UNC5C. DR InterPro; IPR007110; Ig-like_dom. DR InterPro; IPR036179; Ig-like_dom_sf. DR InterPro; IPR013783; Ig-like_fold. DR InterPro; IPR013098; Ig_I-set. DR InterPro; IPR003599; Ig_sub. DR InterPro; IPR003598; Ig_sub2. DR InterPro; IPR000884; TSP1_rpt. DR InterPro; IPR036383; TSP1_rpt_sf. DR InterPro; IPR037936; UNC5A-D. DR InterPro; IPR057755; UNC5A-D-like_N. DR InterPro; IPR033772; UPA. DR InterPro; IPR000906; ZU5_dom. DR PANTHER; PTHR12582; NETRIN RECEPTOR UNC5; 1. DR PANTHER; PTHR12582:SF7; NETRIN RECEPTOR UNC5C; 1. DR Pfam; PF00531; Death; 1. DR Pfam; PF07679; I-set; 1. DR Pfam; PF00090; TSP_1; 2. DR Pfam; PF25609; Unc5_NetrinR_N; 1. DR Pfam; PF17217; UPA; 1. DR Pfam; PF00791; ZU5; 1. DR PRINTS; PR01705; TSP1REPEAT. DR SMART; SM00005; DEATH; 1. DR SMART; SM00409; IG; 1. DR SMART; SM00408; IGc2; 1. DR SMART; SM00209; TSP1; 2. DR SMART; SM00218; ZU5; 1. DR SUPFAM; SSF47986; DEATH domain; 1. DR SUPFAM; SSF48726; Immunoglobulin; 2. DR SUPFAM; SSF82895; TSP-1 type 1 repeat; 2. DR PROSITE; PS50835; IG_LIKE; 1. DR PROSITE; PS50092; TSP1; 2. DR PROSITE; PS51145; ZU5; 1. PE 1: Evidence at protein level; KW Alternative splicing; Alzheimer disease; Amyloidosis; Apoptosis; KW Cell membrane; Cell projection; Developmental protein; Disulfide bond; KW Glycoprotein; Immunoglobulin domain; Membrane; Neurodegeneration; KW Phosphoprotein; Proteomics identification; Receptor; Reference proteome; KW Repeat; Signal; Synapse; Synaptosome; Transmembrane; Transmembrane helix. FT SIGNAL 1..40 FT /evidence="ECO:0000255" FT CHAIN 41..931 FT /note="Netrin receptor UNC5C" FT /id="PRO_0000036075" FT TOPO_DOM 41..380 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 381..401 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 402..931 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 62..159 FT /note="Ig-like" FT DOMAIN 161..256 FT /note="Ig-like C2-type" FT DOMAIN 260..314 FT /note="TSP type-1 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210" FT DOMAIN 316..368 FT /note="TSP type-1 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210" FT DOMAIN 530..673 FT /note="ZU5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00485" FT DOMAIN 850..929 FT /note="Death" FT REGION 402..931 FT /note="Required for netrin-mediated axon repulsion of FT neuronal growth cones" FT /evidence="ECO:0000250|UniProtKB:O08747" FT REGION 694..712 FT /note="Interaction with DCC" FT /evidence="ECO:0000250|UniProtKB:O08747" FT SITE 415..416 FT /note="Cleavage; by caspase-3" FT /evidence="ECO:0000250|UniProtKB:Q761X5" FT MOD_RES 502 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O08747" FT MOD_RES 568 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:O08747" FT CARBOHYD 236 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 361 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 83..144 FT /evidence="ECO:0000250|UniProtKB:Q6ZN44" FT DISULFID 95..142 FT /evidence="ECO:0000250|UniProtKB:Q6ZN44" FT DISULFID 188..239 FT /evidence="ECO:0000250|UniProtKB:Q6ZN44" FT DISULFID 272..309 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210" FT DISULFID 276..313 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210" FT DISULFID 287..299 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210" FT DISULFID 328..362 FT /evidence="ECO:0000250|UniProtKB:Q6ZN44" FT DISULFID 332..367 FT /evidence="ECO:0000250|UniProtKB:Q6ZN44" FT DISULFID 340..352 FT /evidence="ECO:0000250|UniProtKB:Q6ZN44" FT VAR_SEQ 370 FT /note="T -> SFIYPISTEQRTQNEYGFSS (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_011700" FT VAR_SEQ 579..931 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_011701" FT VARIANT 37 FT /note="G -> V (in dbSNP:rs2306715)" FT /id="VAR_019731" FT VARIANT 721 FT /note="M -> T (in dbSNP:rs2289043)" FT /evidence="ECO:0000269|PubMed:9782087" FT /id="VAR_019732" FT VARIANT 835 FT /note="T -> M (in AD; increased susceptibility to neuronal FT cell death; dbSNP:rs137875858)" FT /evidence="ECO:0000269|PubMed:25419706, FT ECO:0000269|PubMed:27068745" FT /id="VAR_081368" FT VARIANT 841 FT /note="A -> T (in dbSNP:rs34585936)" FT /id="VAR_055327" FT CONFLICT 219 FT /note="T -> I (in Ref. 3; AAH41156)" FT /evidence="ECO:0000305" FT CONFLICT 489 FT /note="T -> S (in Ref. 1; AAC67491)" FT /evidence="ECO:0000305" FT CONFLICT 651 FT /note="Q -> K (in Ref. 1; AAC67491)" FT /evidence="ECO:0000305" SQ SEQUENCE 931 AA; 103146 MW; 98A95995129532A7 CRC64; MRKGLRATAA RCGLGLGYLL QMLVLPALAL LSASGTGSAA QDDDFFHELP ETFPSDPPEP LPHFLIEPEE AYIVKNKPVN LYCKASPATQ IYFKCNSEWV HQKDHIVDER VDETSGLIVR EVSIEISRQQ VEELFGPEDY WCQCVAWSSA GTTKSRKAYV RIAYLRKTFE QEPLGKEVSL EQEVLLQCRP PEGIPVAEVE WLKNEDIIDP VEDRNFYITI DHNLIIKQAR LSDTANYTCV AKNIVAKRKS TTATVIVYVN GGWSTWTEWS VCNSRCGRGY QKRTRTCTNP APLNGGAFCE GQSVQKIACT TLCPVDGRWT PWSKWSTCGT ECTHWRRREC TAPAPKNGGK DCDGLVLQSK NCTDGLCMQT APDSDDVALY VGIVIAVIVC LAISVVVALF VYRKNHRDFE SDIIDSSALN GGFQPVNIKA ARQDLLAVPP DLTSAAAMYR GPVYALHDVS DKIPMTNSPI LDPLPNLKIK VYNTSGAVTP QDDLSEFTSK LSPQMTQSLL ENEALSLKNQ SLARQTDPSC TAFGSFNSLG GHLIVPNSGV SLLIPAGAIP QGRVYEMYVT VHRKETMRPP MDDSQTLLTP VVSCGPPGAL LTRPVVLTMH HCADPNTEDW KILLKNQAAQ GQWEDVVVVG EENFTTPCYI QLDAEACHIL TENLSTYALV GHSTTKAAAK RLKLAIFGPL CCSSLEYSIR VYCLDDTQDA LKEILHLERQ MGGQLLEEPK ALHFKGSTHN LRLSIHDIAH SLWKSKLLAK YQEIPFYHVW SGSQRNLHCT FTLERFSLNT VELVCKLCVR QVEGEGQIFQ LNCTVSEEPT GIDLPLLDPA NTITTVTGPS AFSIPLPIRQ KLCSSLDAPQ TRGHDWRMLA HKLNLDRYLN YFATKSSPTG VILDLWEAQN FPDGNLSMLA AVLEEMGRHE TVVSLAAEGQ Y //