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 DHC24_HUMAN Reviewed; 516 AA. AC Q15392; B7Z817; D3DQ51; Q9HBA8; DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot. DT 31-JAN-2002, sequence version 2. DT 28-JAN-2026, entry version 214. DE RecName: Full=Delta(24)-sterol reductase; DE EC=1.3.1.72 {ECO:0000269|PubMed:11519011, ECO:0000269|PubMed:21671375}; DE AltName: Full=24-dehydrocholesterol reductase; DE AltName: Full=3-beta-hydroxysterol Delta-24-reductase; DE AltName: Full=Diminuto/dwarf1 homolog; DE AltName: Full=Seladin-1 {ECO:0000303|PubMed:11007892}; DE Flags: Precursor; GN Name=DHCR24; Synonyms=KIAA0018; 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), FUNCTION, SUBCELLULAR LOCATION, AND RP TISSUE SPECIFICITY. RC TISSUE=Brain; RX PubMed=11007892; DOI=10.1523/jneurosci.20-19-07345.2000; RA Greeve I., Hermans-Borgmeyer I., Brellinger C., Kasper D., Gomez-Isla T., RA Behl C., Levkau B., Nitsch R.M.; RT "The human DIMINUTO/DWARF1 homolog seladin-1 confers resistance to RT Alzheimer's disease-associated neurodegeneration and oxidative stress."; RL J. Neurosci. 20:7345-7352(2000). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, TISSUE SPECIFICITY, VARIANTS RP DESMOS LYS-191; THR-294; ASN-306 AND SER-471, CATALYTIC ACTIVITY, AND RP CHARACTERIZATION OF VARIANTS DESMOS LYS-191; THR-294; ASN-306 AND SER-471. RX PubMed=11519011; DOI=10.1086/323473; RA Waterham H.R., Koster J., Romeijn G.J., Hennekam R.C.M., Vreken P., RA Andersson H.C., FitzPatrick D.R., Kelley R.I., Wanders R.J.A.; RT "Mutations in the 3beta-hydroxysterol delta24-reductase gene cause RT desmosterolosis, an autosomal recessive disorder of cholesterol RT biosynthesis."; RL Am. J. Hum. Genet. 69:685-694(2001). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Bone marrow; RX PubMed=7584026; DOI=10.1093/dnares/1.1.27; RA Nomura N., Miyajima N., Sazuka T., Tanaka A., Kawarabayasi Y., Sato S., RA Nagase T., Seki N., Ishikawa K., Tabata S.; RT "Prediction of the coding sequences of unidentified human genes. I. The RT coding sequences of 40 new genes (KIAA0001-KIAA0040) deduced by analysis of RT randomly sampled cDNA clones from human immature myeloid cell line KG-1."; RL DNA Res. 1:27-35(1994). RN [4] RP SEQUENCE REVISION TO C-TERMINUS. RA Ohara O., Nagase T., Kikuno R., Nomura N.; RL Submitted (JAN-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Testis; 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [7] 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 [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain, 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 [9] RP VARIANTS DESMOS HIS-94 AND LYS-480, CHARACTERIZATION OF VARIANTS DESMOS RP HIS-94 AND LYS-480, CATALYTIC ACTIVITY, AND FUNCTION. RX PubMed=21671375; DOI=10.1002/ajmg.a.34040; RA Schaaf C.P., Koster J., Katsonis P., Kratz L., Shchelochkov O.A., RA Scaglia F., Kelley R.I., Lichtarge O., Waterham H.R., Shinawi M.; RT "Desmosterolosis-phenotypic and molecular characterization of a third case RT and review of the literature."; RL Am. J. Med. Genet. A 155A:1597-1604(2011). RN [10] 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 [11] RP CATALYTIC ACTIVITY, AND FUNCTION. RX PubMed=22178193; DOI=10.1016/j.bbalip.2011.11.009; RA Zerenturk E.J., Kristiana I., Gill S., Brown A.J.; RT "The endogenous regulator 24(S),25-epoxycholesterol inhibits cholesterol RT synthesis at DHCR24 (Seladin-1)."; RL Biochim. Biophys. Acta 1821:1269-1277(2012). RN [12] RP FUNCTION, SUBCELLULAR LOCATION, AND TOPOLOGY. RX PubMed=22010141; DOI=10.1530/jme-11-0132; RA Lu X., Li Y., Liu J., Cao X., Wang X., Wang D., Seo H., Gao B.; RT "The membrane topological analysis of 3 {beta}-hydroxysteroid-delta24 RT reductase (DHCR24) on endoplasmic reticulum."; RL J. Mol. Endocrinol. 48:1-9(2012). RN [13] 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 [14] RP CATALYTIC ACTIVITY, AND INTERACTION WITH DHCR7. RX PubMed=25637936; DOI=10.1194/jlr.m056986; RA Luu W., Hart-Smith G., Sharpe L.J., Brown A.J.; RT "The terminal enzymes of cholesterol synthesis, DHCR24 and DHCR7, interact RT physically and functionally."; RL J. Lipid Res. 56:888-897(2015). 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). CC -!- FUNCTION: Catalyzes the reduction of the delta-24 double bond of sterol CC intermediates during cholesterol biosynthesis (PubMed:11519011, CC PubMed:21671375, PubMed:22178193, PubMed:25637936). In addition to its CC cholesterol-synthesizing activity, can protect cells from oxidative CC stress by reducing caspase 3 activity during apoptosis induced by CC oxidative stress (PubMed:11007892, PubMed:22010141). Also protects CC against amyloid-beta peptide-induced apoptosis (PubMed:11007892). CC {ECO:0000269|PubMed:11007892, ECO:0000269|PubMed:11519011, CC ECO:0000269|PubMed:21671375, ECO:0000269|PubMed:22010141, CC ECO:0000269|PubMed:22178193, ECO:0000269|PubMed:25637936}. CC -!- CATALYTIC ACTIVITY: CC Reaction=cholesterol + NADP(+) = desmosterol + NADPH + H(+); CC Xref=Rhea:RHEA:36391, ChEBI:CHEBI:15378, ChEBI:CHEBI:16113, CC ChEBI:CHEBI:17737, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.3.1.72; CC Evidence={ECO:0000269|PubMed:11519011, ECO:0000269|PubMed:21671375, CC ECO:0000269|PubMed:25637936}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:36393; CC Evidence={ECO:0000305|PubMed:11519011, ECO:0000305|PubMed:21671375}; CC -!- CATALYTIC ACTIVITY: CC Reaction=lanosterol + NADPH + H(+) = 24,25-dihydrolanosterol + NADP(+); CC Xref=Rhea:RHEA:33919, ChEBI:CHEBI:15378, ChEBI:CHEBI:16521, CC ChEBI:CHEBI:28113, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; CC Evidence={ECO:0000269|PubMed:22178193}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33920; CC Evidence={ECO:0000269|PubMed:22178193}; CC -!- CATALYTIC ACTIVITY: CC Reaction=5alpha-cholest-8-en-3beta-ol + NADP(+) = zymosterol + NADPH + CC H(+); Xref=Rhea:RHEA:36399, ChEBI:CHEBI:15378, ChEBI:CHEBI:16608, CC ChEBI:CHEBI:18252, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.3.1.72; CC Evidence={ECO:0000250|UniProtKB:Q8VCH6}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:36401; CC Evidence={ECO:0000250|UniProtKB:Q8VCH6}; CC -!- COFACTOR: CC Name=FAD; Xref=ChEBI:CHEBI:57692; CC -!- PATHWAY: Steroid biosynthesis; cholesterol biosynthesis. CC {ECO:0000269|PubMed:11519011, ECO:0000269|PubMed:21671375}. CC -!- SUBUNIT: Interacts with DHCR7; this interaction regulates DHCR7 CC activity. {ECO:0000269|PubMed:25637936}. CC -!- INTERACTION: CC Q15392; O00264: PGRMC1; NbExp=2; IntAct=EBI-5457558, EBI-1045534; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:11007892, ECO:0000269|PubMed:22010141}; Single-pass CC membrane protein {ECO:0000255}. Golgi apparatus membrane CC {ECO:0000269|PubMed:11007892}; Single-pass membrane protein CC {ECO:0000255}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q15392-1; Sequence=Displayed; CC Name=2; CC IsoId=Q15392-2; Sequence=VSP_056479; CC -!- TISSUE SPECIFICITY: Highly expressed in brain and adrenal gland with CC moderate expression in liver, lung, spleen, prostate and spinal cord. CC Low expression in heart, uterus and prostate. Undetectable in blood CC cells. In the brain, strongly expressed in cortical regions, substantia CC nigra, caudate nucleus, hippocampus, medulla oblongata and pons. In CC brains affected by Alzheimer disease, expression in the inferior CC temporal lobe is substantially lower than in the frontal cortex. CC {ECO:0000269|PubMed:11007892, ECO:0000269|PubMed:11519011}. CC -!- DISEASE: Desmosterolosis (DESMOS) [MIM:602398]: Rare autosomal CC recessive disorder characterized by multiple congenital anomalies and CC elevated levels of the cholesterol precursor desmosterol in plasma, CC tissue, and cultured cells. {ECO:0000269|PubMed:11519011, CC ECO:0000269|PubMed:21671375}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the FAD-binding oxidoreductase/transferase type CC 4 family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAA02806.3; Type=Erroneous initiation; Note=Extended N-terminus.; 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; AF261758; AAG17288.1; -; mRNA. DR EMBL; AF398342; AAL15644.1; -; Genomic_DNA. DR EMBL; AF398336; AAL15644.1; JOINED; Genomic_DNA. DR EMBL; AF398337; AAL15644.1; JOINED; Genomic_DNA. DR EMBL; AF398338; AAL15644.1; JOINED; Genomic_DNA. DR EMBL; AF398339; AAL15644.1; JOINED; Genomic_DNA. DR EMBL; AF398340; AAL15644.1; JOINED; Genomic_DNA. DR EMBL; AF398341; AAL15644.1; JOINED; Genomic_DNA. DR EMBL; D13643; BAA02806.3; ALT_INIT; mRNA. DR EMBL; AK302774; BAH13803.1; -; mRNA. DR EMBL; AC096536; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471059; EAX06663.1; -; Genomic_DNA. DR EMBL; CH471059; EAX06664.1; -; Genomic_DNA. DR EMBL; BC004375; AAH04375.1; -; mRNA. DR EMBL; BC011669; AAH11669.1; -; mRNA. DR CCDS; CCDS600.1; -. [Q15392-1] DR RefSeq; NP_055577.1; NM_014762.4. [Q15392-1] DR AlphaFoldDB; Q15392; -. DR SMR; Q15392; -. DR BioGRID; 108064; 217. DR CORUM; Q15392; -. DR FunCoup; Q15392; 1145. DR IntAct; Q15392; 154. DR MINT; Q15392; -. DR STRING; 9606.ENSP00000360316; -. DR BindingDB; Q15392; -. DR ChEMBL; CHEMBL2331059; -. DR DrugCentral; Q15392; -. DR SwissLipids; SLP:000001223; -. DR GlyGen; Q15392; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q15392; -. DR MetOSite; Q15392; -. DR PhosphoSitePlus; Q15392; -. DR SwissPalm; Q15392; -. DR BioMuta; DHCR24; -. DR DMDM; 20141421; -. DR jPOST; Q15392; -. DR MassIVE; Q15392; -. DR PaxDb; 9606-ENSP00000360316; -. DR PeptideAtlas; Q15392; -. DR ProteomicsDB; 60562; -. [Q15392-1] DR ProteomicsDB; 6916; -. DR Pumba; Q15392; -. DR Antibodypedia; 33226; 239 antibodies from 30 providers. DR DNASU; 1718; -. DR Ensembl; ENST00000371269.9; ENSP00000360316.3; ENSG00000116133.14. [Q15392-1] DR Ensembl; ENST00000436604.2; ENSP00000416585.2; ENSG00000116133.14. [Q15392-1] DR GeneID; 1718; -. DR KEGG; hsa:1718; -. DR MANE-Select; ENST00000371269.9; ENSP00000360316.3; NM_014762.4; NP_055577.1. DR UCSC; uc001cyc.2; human. [Q15392-1] DR AGR; HGNC:2859; -. DR ClinPGx; PA27320; -. DR CTD; 1718; -. DR DisGeNET; 1718; -. DR GeneCards; DHCR24; -. DR HGNC; HGNC:2859; DHCR24. DR HPA; ENSG00000116133; Tissue enhanced (adrenal gland, liver). DR MalaCards; DHCR24; -. DR MIM; 602398; phenotype. DR MIM; 606418; gene. DR OpenTargets; ENSG00000116133; -. DR Orphanet; 35107; Desmosterolosis. DR VEuPathDB; HostDB:ENSG00000116133; -. DR eggNOG; KOG1262; Eukaryota. DR GeneTree; ENSGT00390000008338; -. DR InParanoid; Q15392; -. DR OrthoDB; 415825at2759; -. DR PAN-GO; Q15392; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q15392; -. DR BRENDA; 1.3.1.72; 2681. DR PathwayCommons; Q15392; -. DR Reactome; R-HSA-191273; Cholesterol biosynthesis. DR Reactome; R-HSA-6807047; Cholesterol biosynthesis via desmosterol. DR Reactome; R-HSA-6807062; Cholesterol biosynthesis via lathosterol. DR SignaLink; Q15392; -. DR SIGNOR; Q15392; -. DR UniPathway; UPA00063; -. DR Agora; ENSG00000116133; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 1718; 22 hits in 1166 CRISPR screens. DR ChiTaRS; DHCR24; human. DR GeneWiki; 24-dehydrocholesterol_reductase; -. DR GenomeRNAi; 1718; -. DR Pharos; Q15392; Tchem. DR PRO; PR:Q15392; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q15392; protein. DR Bgee; ENSG00000116133; Expressed in adrenal tissue and 197 other cell types or tissues. DR ExpressionAtlas; Q15392; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0000246; F:Delta24(24-1) sterol reductase activity; IMP:UniProtKB. DR GO; GO:0050614; F:Delta24-sterol reductase activity; EXP:Reactome. DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB. DR GO; GO:0071949; F:FAD binding; IEA:InterPro. DR GO; GO:0016628; F:oxidoreductase activity, acting on the CH-CH group of donors, NAD or NADP as acceptor; IDA:MGI. DR GO; GO:0042605; F:peptide antigen binding; IPI:UniProtKB. DR GO; GO:0042987; P:amyloid precursor protein catabolic process; IEA:Ensembl. DR GO; GO:0006695; P:cholesterol biosynthetic process; IMP:MGI. DR GO; GO:0033489; P:cholesterol biosynthetic process via desmosterol; IMP:UniProtKB. DR GO; GO:0033490; P:cholesterol biosynthetic process via lathosterol; TAS:Reactome. DR GO; GO:0008104; P:intracellular protein localization; IEA:Ensembl. DR GO; GO:0030539; P:male genitalia development; IEA:Ensembl. DR GO; GO:0061024; P:membrane organization; IEA:Ensembl. DR GO; GO:0008285; P:negative regulation of cell population proliferation; IEA:Ensembl. DR GO; GO:0031639; P:plasminogen activation; IEA:Ensembl. DR GO; GO:0007265; P:Ras protein signal transduction; IEA:Ensembl. DR GO; GO:0009725; P:response to hormone; IEA:Ensembl. DR GO; GO:0043588; P:skin development; ISS:UniProtKB. DR GO; GO:0008202; P:steroid metabolic process; IBA:GO_Central. DR GO; GO:0009888; P:tissue development; IMP:UniProtKB. DR FunFam; 3.30.465.10:FF:000032; Delta(24)-sterol reductase; 1. DR Gene3D; 3.30.465.10; -; 1. DR InterPro; IPR040165; Diminuto-like. DR InterPro; IPR016166; FAD-bd_PCMH. DR InterPro; IPR036318; FAD-bd_PCMH-like_sf. DR InterPro; IPR016169; FAD-bd_PCMH_sub2. DR InterPro; IPR006094; Oxid_FAD_bind_N. DR PANTHER; PTHR10801; 24-DEHYDROCHOLESTEROL REDUCTASE; 1. DR PANTHER; PTHR10801:SF0; DELTA(24)-STEROL REDUCTASE; 1. DR Pfam; PF01565; FAD_binding_4; 1. DR SUPFAM; SSF56176; FAD-binding/transporter-associated domain-like; 1. DR PROSITE; PS51387; FAD_PCMH; 1. PE 1: Evidence at protein level; KW Alternative splicing; Cholesterol biosynthesis; Cholesterol metabolism; KW Disease variant; Endoplasmic reticulum; FAD; Flavoprotein; Golgi apparatus; KW Lipid biosynthesis; Lipid metabolism; Membrane; NADP; Oxidoreductase; KW Proteomics identification; Reference proteome; Signal; KW Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis; KW Sterol metabolism; Transmembrane; Transmembrane helix. FT SIGNAL 1..22 FT /evidence="ECO:0000255" FT CHAIN 23..516 FT /note="Delta(24)-sterol reductase" FT /id="PRO_0000007230" FT TOPO_DOM 23..31 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:22010141" FT TRANSMEM 32..52 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 53..516 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:22010141" FT DOMAIN 58..234 FT /note="FAD-binding PCMH-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00718" FT BINDING 163..175 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000255" FT SITE 122..123 FT /note="Cleavage; by caspase" FT /evidence="ECO:0000255" FT SITE 383..384 FT /note="Cleavage; by caspase" FT /evidence="ECO:0000255" FT VAR_SEQ 1..76 FT /note="MEPAVSLAVCALLFLLWVRLKGLEFVLIHQRWVFVCLFLLPLSLIFDIYYYV FT RAWVVFKLSSAPRLHEQRVRDIQK -> MGAGEQNRQSAHCVQGICGYLEGDEEGEEGE FT VRST (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_056479" FT VARIANT 94 FT /note="R -> H (in DESMOS; decreases production of FT cholesterol from desmosterol; dbSNP:rs387906939)" FT /evidence="ECO:0000269|PubMed:21671375" FT /id="VAR_081889" FT VARIANT 191 FT /note="E -> K (in DESMOS; decreases production of FT cholesterol from desmosterol; dbSNP:rs119475041)" FT /evidence="ECO:0000269|PubMed:11519011" FT /id="VAR_012732" FT VARIANT 294 FT /note="N -> T (in DESMOS; decreases production of FT cholesterol from desmosterol; dbSNP:rs281797257)" FT /evidence="ECO:0000269|PubMed:11519011" FT /id="VAR_012733" FT VARIANT 306 FT /note="K -> N (in DESMOS; decreases production of FT cholesterol from desmosterol; dbSNP:rs281797256)" FT /evidence="ECO:0000269|PubMed:11519011" FT /id="VAR_012734" FT VARIANT 471 FT /note="Y -> S (in DESMOS; complete loss of ability to FT convert desmosterol to cholesterol; dbSNP:rs28939092)" FT /evidence="ECO:0000269|PubMed:11519011, FT ECO:0000269|PubMed:21671375" FT /id="VAR_012735" FT VARIANT 480 FT /note="E -> K (in DESMOS; decreases production of FT cholesterol from desmosterol; dbSNP:rs387906940)" FT /evidence="ECO:0000269|PubMed:21671375" FT /id="VAR_081890" SQ SEQUENCE 516 AA; 60101 MW; F9A769446FE19E59 CRC64; MEPAVSLAVC ALLFLLWVRL KGLEFVLIHQ RWVFVCLFLL PLSLIFDIYY YVRAWVVFKL SSAPRLHEQR VRDIQKQVRE WKEQGSKTFM CTGRPGWLTV SLRVGKYKKT HKNIMINLMD ILEVDTKKQI VRVEPLVTMG QVTALLTSIG WTLPVLPELD DLTVGGLIMG TGIESSSHKY GLFQHICTAY ELVLADGSFV RCTPSENSDL FYAVPWSCGT LGFLVAAEIR IIPAKKYVKL RFEPVRGLEA ICAKFTHESQ RQENHFVEGL LYSLDEAVIM TGVMTDEAEP SKLNSIGNYY KPWFFKHVEN YLKTNREGLE YIPLRHYYHR HTRSIFWELQ DIIPFGNNPI FRYLFGWMVP PKISLLKLTQ GETLRKLYEQ HHVVQDMLVP MKCLQQALHT FQNDIHVYPI WLCPFILPSQ PGLVHPKGNE AELYIDIGAY GEPRVKHFEA RSCMRQLEKF VRSVHGFQML YADCYMNREE FWEMFDGSLY HKLREKLGCQ DAFPEVYDKI CKAARH // 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 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 PSCA_HUMAN Reviewed; 114 AA. AC O43653; Q6UW92; DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot. DT 10-OCT-2018, sequence version 2. DT 28-JAN-2026, entry version 188. DE RecName: Full=Prostate stem cell antigen; DE Flags: Precursor; GN Name=PSCA; ORFNames=UNQ206/PRO232; 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], SUBCELLULAR LOCATION, AND GLYCOSYLATION. RC TISSUE=Prostatic carcinoma; RX PubMed=9465086; DOI=10.1073/pnas.95.4.1735; RA Reiter R.E., Gu Z., Watabe T., Thomas G., Szigeti K., Davis E., Wahl M., RA Nisitani S., Yamashiro J., le Beau M.M., Losa M., Witte O.N.; RT "Prostate stem cell antigen: a cell surface marker overexpressed in RT prostate cancer."; RL Proc. Natl. Acad. Sci. U.S.A. 95:1735-1740(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Urothelium; RX PubMed=10973799; DOI=10.1006/bbrc.2000.3393; RA Bahrenberg G., Brauers A., Joost H.G., Jakse G.; RT "Reduced expression of PSCA, a member of the LY-6 family of cell surface RT antigens, in bladder, esophagus, and stomach tumors."; RL Biochem. Biophys. Res. Commun. 275:783-788(2000). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16421571; DOI=10.1038/nature04406; RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M., RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L., RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S., RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A., RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III, RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., RA Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P., RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H., RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B., RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K., RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L., RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G., RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W., RA Platzer M., Shimizu N., Lander E.S.; RT "DNA sequence and analysis of human chromosome 8."; RL Nature 439:331-335(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Melanoma; 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 PROTEIN SEQUENCE OF 12-26. RX PubMed=15340161; DOI=10.1110/ps.04682504; RA Zhang Z., Henzel W.J.; RT "Signal peptide prediction based on analysis of experimentally verified RT cleavage sites."; RL Protein Sci. 13:2819-2824(2004). RN [7] RP TISSUE SPECIFICITY. RX PubMed=10713670; DOI=10.1038/sj.onc.1203426; RA Gu Z., Thomas G., Yamashiro J., Shintaku I.P., Dorey F., Raitano A., RA Witte O.N., Said J.W., Loda M., Reiter R.E.; RT "Prostate stem cell antigen (PSCA) expression increases with high gleason RT score, advanced stage and bone metastasis in prostate cancer."; RL Oncogene 19:1288-1296(2000). RN [8] RP FUNCTION, TISSUE SPECIFICITY, INDUCTION, ASSOCIATION WITH SUSCEPTIBILITY TO RP DIFFUSE-TYPE GASTRIC CANCER, AND VARIANT LYS-30. RX PubMed=18488030; DOI=10.1038/ng.152; RG The study group of millennium genome project for cancer; RA Sakamoto H., Yoshimura K., Saeki N., Katai H., Shimoda T., Matsuno Y., RA Saito D., Sugimura H., Tanioka F., Kato S., Matsukura N., Matsuda N., RA Nakamura T., Hyodo I., Nishina T., Yasui W., Hirose H., Hayashi M., RA Toshiro E., Ohnami S., Sekine A., Sato Y., Totsuka H., Ando M., RA Takemura R., Takahashi Y., Ohdaira M., Aoki K., Honmyo I., Chiku S., RA Aoyagi K., Sasaki H., Ohnami S., Yanagihara K., Yoon K.-A., Kook M.-C., RA Lee Y.-S., Park S.R., Kim C.G., Choi I.J., Yoshida T., Nakamura Y., RA Hirohashi S.; RT "Genetic variation in PSCA is associated with susceptibility to diffuse- RT type gastric cancer."; RL Nat. Genet. 40:730-740(2008). RN [9] RP ASSOCIATION WITH SUSCEPTIBILITY TO URINARY BLADDER CANCER. RX PubMed=19648920; DOI=10.1038/ng.421; RA Wu X., Ye Y., Kiemeney L.A., Sulem P., Rafnar T., Matullo G., Seminara D., RA Yoshida T., Saeki N., Andrew A.S., Dinney C.P., Czerniak B., Zhang Z.F., RA Kiltie A.E., Bishop D.T., Vineis P., Porru S., Buntinx F., Kellen E., RA Zeegers M.P., Kumar R., Rudnai P., Gurzau E., Koppova K., Mayordomo J.I., RA Sanchez M., Saez B., Lindblom A., de Verdier P., Steineck G., Mills G.B., RA Schned A., Guarrera S., Polidoro S., Chang S.C., Lin J., Chang D.W., RA Hale K.S., Majewski T., Grossman H.B., Thorlacius S., Thorsteinsdottir U., RA Aben K.K., Witjes J.A., Stefansson K., Amos C.I., Karagas M.R., Gu J.; RT "Genetic variation in the prostate stem cell antigen gene PSCA confers RT susceptibility to urinary bladder cancer."; RL Nat. Genet. 41:991-995(2009). RN [10] RP FUNCTION, INTERACTION WITH CHRNA4, AND TISSUE SPECIFICITY. RX PubMed=25680266; DOI=10.1016/j.neurobiolaging.2015.01.001; RA Jensen M.M., Arvaniti M., Mikkelsen J.D., Michalski D., Pinborg L.H., RA Haertig W., Thomsen M.S.; RT "Prostate stem cell antigen interacts with nicotinic acetylcholine RT receptors and is affected in Alzheimer's disease."; RL Neurobiol. Aging 36:1629-1638(2015). CC -!- FUNCTION: May be involved in the regulation of cell proliferation. Has CC a cell-proliferation inhibition activity in vitro. CC {ECO:0000269|PubMed:18488030}. CC -!- FUNCTION: May act as a modulator of nicotinic acetylcholine receptors CC (nAChRs) activity. In vitro inhibits nicotine-induced signaling CC probably implicating alpha-3:beta-2- or alpha-7-containing nAChRs. CC {ECO:0000305|PubMed:25680266}. CC -!- SUBUNIT: Interacts with CHRNA4. {ECO:0000269|PubMed:25680266}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:9465086}; CC Lipid-anchor, GPI-anchor {ECO:0000269|PubMed:9465086}. CC -!- TISSUE SPECIFICITY: Highly expressed in prostate (basal, secretory and CC neuroendocrine epithelium cells). Also found in bladder (transitional CC epithelium), placenta (trophoblasts), stomach (neuroendocrine cells), CC colon (neuroendocrine cells) and kidney (collecting ducts). CC Overexpressed in prostate cancers and expression is correlated with CC tumor stage, grade and androgen-independence. Highly expressed in CC prostate cancer bone metastases. Expressed in gastric epithelial cells, CC mainly in the isthmus (at protein level). Not detected in normal CC intestinal epithelium (at protein level). Expressed in brain cortex; CC expression is significantly increased in the front cortex of Alzheimer CC disease patients. {ECO:0000269|PubMed:10713670, CC ECO:0000269|PubMed:18488030, ECO:0000269|PubMed:25680266}. CC -!- INDUCTION: Down-regulated in gastric cancer cells. CC {ECO:0000269|PubMed:18488030}. CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:9465086}. CC -!- POLYMORPHISM: Genetic variations in PSCA may influence susceptibility CC to some cancers. A polymorphism gives rise to an upstream methionine CC which produces a longer protein of 123 residues associated with various CC cancers including diffuse-type gastric cancer and urinary bladder CC cancer. {ECO:0000269|PubMed:18488030, ECO:0000269|PubMed:19648920}. CC -!- SEQUENCE CAUTION: CC Sequence=AAC39607.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH23582.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH65183.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAQ89271.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=CAB97347.1; 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/41881/PSCA"; 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; AF043498; AAC39607.1; ALT_INIT; mRNA. DR EMBL; AJ297436; CAB97347.1; ALT_INIT; mRNA. DR EMBL; AC108002; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AY358912; AAQ89271.1; ALT_INIT; mRNA. DR EMBL; BC023582; AAH23582.1; ALT_INIT; mRNA. DR EMBL; BC065183; AAH65183.1; ALT_INIT; mRNA. DR CCDS; CCDS47925.2; -. DR RefSeq; NP_005663.2; NM_005672.5. DR AlphaFoldDB; O43653; -. DR SMR; O43653; -. DR FunCoup; O43653; 88. DR IntAct; O43653; 105. DR STRING; 9606.ENSP00000301258; -. DR ChEMBL; CHEMBL3712961; -. DR DrugBank; DB05933; MK-4721. DR GlyCosmos; O43653; 1 site, No reported glycans. DR GlyGen; O43653; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; O43653; -. DR PhosphoSitePlus; O43653; -. DR BioMuta; PSCA; -. DR jPOST; O43653; -. DR MassIVE; O43653; -. DR PaxDb; 9606-ENSP00000301258; -. DR PeptideAtlas; O43653; -. DR ProteomicsDB; 49089; -. DR Pumba; O43653; -. DR Antibodypedia; 7385; 411 antibodies from 40 providers. DR DNASU; 8000; -. DR Ensembl; ENST00000301258.5; ENSP00000301258.4; ENSG00000167653.6. DR GeneID; 8000; -. DR KEGG; hsa:8000; -. DR MANE-Select; ENST00000301258.5; ENSP00000301258.4; NM_005672.5; NP_005663.2. DR UCSC; uc003ywu.4; human. DR AGR; HGNC:9500; -. DR CTD; 8000; -. DR DisGeNET; 8000; -. DR GeneCards; PSCA; -. DR HGNC; HGNC:9500; PSCA. DR HPA; ENSG00000167653; Tissue enriched (stomach). DR MIM; 602470; gene. DR OpenTargets; ENSG00000167653; -. DR VEuPathDB; HostDB:ENSG00000167653; -. DR eggNOG; ENOG502SCWD; Eukaryota. DR GeneTree; ENSGT00940000153378; -. DR HOGENOM; CLU_141358_1_0_1; -. DR InParanoid; O43653; -. DR OMA; ISKGCTS; -. DR OrthoDB; 5945173at2759; -. DR PAN-GO; O43653; 2 GO annotations based on evolutionary models. DR PhylomeDB; O43653; -. DR PathwayCommons; O43653; -. DR Reactome; R-HSA-163125; Post-translational modification: synthesis of GPI-anchored proteins. DR SignaLink; O43653; -. DR Agora; ENSG00000167653; -. DR ChiTaRS; PSCA; human. DR Pharos; O43653; Tbio. DR PRO; PR:O43653; -. DR Proteomes; UP000005640; Chromosome 8. DR RNAct; O43653; protein. DR Bgee; ENSG00000167653; Expressed in lower esophagus mucosa and 94 other cell types or tissues. DR ExpressionAtlas; O43653; baseline and differential. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. 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; IEA:GOC. DR GO; GO:0033130; F:acetylcholine receptor binding; IDA:UniProtKB. DR GO; GO:0030548; F:acetylcholine receptor regulator activity; IBA:GO_Central. DR GO; GO:0095500; P:acetylcholine receptor signaling pathway; IBA:GO_Central. DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; IDA:UniProtKB. DR GO; GO:0099601; P:regulation of neurotransmitter receptor activity; IDA:UniProtKB. DR CDD; cd23573; TFP_LU_ECD_PSCA; 1. DR FunFam; 2.10.60.10:FF:000003; lymphocyte antigen 6E isoform X1; 1. DR Gene3D; 2.10.60.10; CD59; 1. DR InterPro; IPR051110; Ly-6/neurotoxin-like_GPI-ap. DR InterPro; IPR016054; LY6_UPA_recep-like. DR InterPro; IPR045860; Snake_toxin-like_sf. DR InterPro; IPR035076; Toxin/TOLIP. DR PANTHER; PTHR16983:SF1; PROSTATE STEM CELL ANTIGEN; 1. DR PANTHER; PTHR16983; UPAR/LY6 DOMAIN-CONTAINING PROTEIN; 1. DR Pfam; PF00087; Toxin_TOLIP; 1. DR SMART; SM00134; LU; 1. DR SUPFAM; SSF57302; Snake toxin-like; 1. PE 1: Evidence at protein level; KW Cell membrane; Direct protein sequencing; Disulfide bond; Glycoprotein; KW GPI-anchor; Lipoprotein; Membrane; Proteomics identification; KW Reference proteome; Signal. FT SIGNAL 1..11 FT /evidence="ECO:0000269|PubMed:15340161" FT CHAIN 12..83 FT /note="Prostate stem cell antigen" FT /evidence="ECO:0000255" FT /id="PRO_0000036162" FT PROPEP 84..114 FT /note="Removed in mature form" FT /evidence="ECO:0000255" FT /id="PRO_0000036163" FT DOMAIN 12..98 FT /note="UPAR/Ly6" FT /evidence="ECO:0000255" FT LIPID 83 FT /note="GPI-anchor amidated cysteine" FT /evidence="ECO:0000255" FT CARBOHYD 31 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 14..39 FT /evidence="ECO:0000250|UniProtKB:P0DP57" FT DISULFID 17..26 FT /evidence="ECO:0000250|UniProtKB:P0DP57" FT DISULFID 32..57 FT /evidence="ECO:0000250|UniProtKB:P0DP57" FT DISULFID 61..77 FT /evidence="ECO:0000250|UniProtKB:P0DP57" FT DISULFID 78..83 FT /evidence="ECO:0000250|UniProtKB:P0DP57" FT VARIANT 1 FT /note="M -> MKAVLLALLM (in dbSNP:rs2294008)" FT /evidence="ECO:0000269|PubMed:18488030, FT ECO:0000269|PubMed:19648920" FT /id="VAR_080777" FT VARIANT 30 FT /note="E -> K (in dbSNP:rs3736001)" FT /evidence="ECO:0000269|PubMed:18488030" FT /id="VAR_020173" FT CONFLICT 1 FT /note="M -> T (in Ref. 3; AC108002)" FT /evidence="ECO:0000305" SQ SEQUENCE 114 AA; 11959 MW; 65B3683767990740 CRC64; MAGLALQPGT ALLCYSCKAQ VSNEDCLQVE NCTQLGEQCW TARIRAVGLL TVISKGCSLN CVDDSQDYYV GKKNITCCDT DLCNASGAHA LQPAAAILAL LPALGLLLWG PGQL // 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 TEFF2_HUMAN Reviewed; 374 AA. AC Q9UIK5; Q2FA44; Q4ZFW4; Q53H90; Q53RE1; Q8N2R5; Q9NR15; Q9NSS5; Q9P2Y9; AC Q9UK65; DT 19-JUL-2005, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-2000, sequence version 1. DT 28-JAN-2026, entry version 188. DE RecName: Full=Tomoregulin-2; DE Short=TR-2; DE AltName: Full=Hyperplastic polyposis protein 1; DE AltName: Full=Transmembrane protein with EGF-like and two follistatin-like domains; DE Flags: Precursor; GN Name=TMEFF2; Synonyms=HPP1, TENB2, TPEF; ORFNames=UNQ178/PRO204; 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), FUNCTION, AND TISSUE SPECIFICITY. RC TISSUE=Brain; RX PubMed=10903839; DOI=10.1006/geno.2000.6228; RA Horie M., Mitsumoto Y., Kyushiki H., Kanemoto N., Watanabe A., RA Taniguchi Y., Nishino N., Okamoto T., Kondo M., Mori T., Noguchi K., RA Nakamura Y., Takahashi E., Tanigami A.; RT "Identification and characterization of TMEFF2, a novel survival factor for RT hippocampal and mesencephalic neurons."; RL Genomics 67:146-152(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), NUCLEOTIDE SEQUENCE [GENOMIC DNA] RP OF 1-57, INDUCTION, AND TISSUE SPECIFICITY. RC TISSUE=Brain; RX PubMed=10987305; RA Liang G., Robertson K.D., Talmadge C., Sumegi J., Jones P.A.; RT "The gene for a novel transmembrane protein containing epidermal growth RT factor and follistatin domains is frequently hypermethylated in human tumor RT cells."; RL Cancer Res. 60:4907-4912(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), GLYCOSYLATION, AND TISSUE RP SPECIFICITY. RC TISSUE=Prostatic carcinoma; RX PubMed=11668495; DOI=10.1002/ijc.1450; RA Glynne-Jones E., Harper M.E., Seery L.T., James R., Anglin I., Morgan H.E., RA Taylor K.M., Gee J.M., Nicholson R.I.; RT "TENB2, a proteoglycan identified in prostate cancer that is associated RT with disease progression and androgen independence."; RL Int. J. Cancer 94:178-184(2001). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), AND TISSUE SPECIFICITY. RX PubMed=16439095; DOI=10.1016/j.ygeno.2005.12.004; RA Quayle S.N., Sadar M.D.; RT "A truncated isoform of TMEFF2 encodes a secreted protein in prostate RT cancer cells."; RL Genomics 87:633-637(2006). RN [5] 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=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 [7] 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 [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., RA Tanaka A., Yokoyama S.; RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=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 [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 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 NUCLEOTIDE SEQUENCE [MRNA] OF 1-360. RX PubMed=10600548; DOI=10.1006/bbrc.1999.1873; RA Uchida T., Wada K., Akamatsu T., Yonezawa M., Noguchi H., Mizoguchi A., RA Kasuga M., Sakamoto C.; RT "A novel epidermal growth factor-like molecule containing two follistatin RT modules stimulates tyrosine phosphorylation of erbB-4 in MKN28 gastric RT cancer cells."; RL Biochem. Biophys. Res. Commun. 266:593-602(1999). RN [13] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-57, TISSUE SPECIFICITY, AND RP INDUCTION. RC TISSUE=Colon; RX PubMed=11120884; DOI=10.1073/pnas.98.1.265; RA Young J., Biden K.G., Simms L.A., Huggard P., Karamatic R., Eyre H.J., RA Sutherland G.R., Herath N., Barker M., Anderson G.J., Fitzpatrick D.R., RA Ramm G.A., Jass J.R., Leggett B.A.; RT "HPP1: a transmembrane protein-encoding gene commonly methylated in RT colorectal polyps and cancers."; RL Proc. Natl. Acad. Sci. U.S.A. 98:265-270(2001). RN [14] RP PROTEIN SEQUENCE OF 41-55. RX PubMed=15340161; DOI=10.1110/ps.04682504; RA Zhang Z., Henzel W.J.; RT "Signal peptide prediction based on analysis of experimentally verified RT cleavage sites."; RL Protein Sci. 13:2819-2824(2004). RN [15] RP TISSUE SPECIFICITY. RX PubMed=16805794; DOI=10.1111/j.1471-4159.2006.03801.x; RA Siegel D.A., Davies P., Dobrenis K., Huang M.; RT "Tomoregulin-2 is found extensively in plaques in Alzheimer's disease RT brain."; RL J. Neurochem. 98:34-44(2006). RN [16] RP CLEAVAGE, AND FUNCTION. RX PubMed=17942404; DOI=10.1074/jbc.m702170200; RA Ali N., Knaeuper V.; RT "Phorbol ester-induced shedding of the prostate cancer marker transmembrane RT protein with epidermal growth factor and two follistatin motifs 2 is RT mediated by the disintegrin and metalloproteinase-17."; RL J. Biol. Chem. 282:37378-37388(2007). RN [17] RP GLYCOSYLATION AT ASN-204. RX PubMed=19139490; DOI=10.1074/mcp.m800504-mcp200; RA Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F., Zheng Z.B., RA Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y., Zhang Y.K., Deng Y.L., RA Ying W.T., He S.M., Qian X.H.; RT "A strategy for precise and large scale identification of core fucosylated RT glycoproteins."; RL Mol. Cell. Proteomics 8:913-923(2009). CC -!- FUNCTION: May be a survival factor for hippocampal and mesencephalic CC neurons. The shedded form up-regulates cancer cell proliferation, CC probably by promoting ERK1/2 phosphorylation. CC {ECO:0000269|PubMed:10903839, ECO:0000269|PubMed:17942404}. CC -!- INTERACTION: CC Q9UIK5; PRO_0000000090 [P05067]: APP; NbExp=3; IntAct=EBI-11423693, EBI-21194918; CC Q9UIK5; O75031: HSF2BP; NbExp=3; IntAct=EBI-11423693, EBI-7116203; CC Q9UIK5; P0DPK4: NOTCH2NLC; NbExp=3; IntAct=EBI-11423693, EBI-22310682; CC Q9UIK5; Q7Z5B4-5: RIC3; NbExp=3; IntAct=EBI-11423693, EBI-12375429; CC Q9UIK5; Q96Q45-2: TMEM237; NbExp=3; IntAct=EBI-11423693, EBI-10982110; CC Q9UIK5; P34981: TRHR; NbExp=3; IntAct=EBI-11423693, EBI-18055230; CC Q9UIK5; Q9Y5Z9: UBIAD1; NbExp=3; IntAct=EBI-11423693, EBI-2819725; CC Q9UIK5; Q96MV8: ZDHHC15; NbExp=3; IntAct=EBI-11423693, EBI-12837904; CC Q9UIK5-2; P55212: CASP6; NbExp=3; IntAct=EBI-25835153, EBI-718729; CC Q9UIK5-2; O75400-2: PRPF40A; NbExp=3; IntAct=EBI-25835153, EBI-5280197; CC Q9UIK5-2; P62826: RAN; NbExp=3; IntAct=EBI-25835153, EBI-286642; CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Membrane {ECO:0000305}; Single-pass CC type I membrane protein {ECO:0000305}. CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Membrane {ECO:0000305}; Single-pass CC type I membrane protein {ECO:0000305}. CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Secreted. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q9UIK5-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9UIK5-2; Sequence=VSP_014312, VSP_014313; CC Name=3; Synonyms=TMEFF2-S; CC IsoId=Q9UIK5-3; Sequence=VSP_024973, VSP_024974; CC -!- TISSUE SPECIFICITY: Highly expressed in adult and fetal brain, spinal CC cord and prostate. Expressed in all brain regions except the pituitary CC gland, with highest levels in amygdala and corpus callosum. Expressed CC in the pericryptal myofibroblasts and other stromal cells of normal CC colonic mucosa. Expressed in prostate carcinoma. Down-regulated in CC colorectal cancer. Present in Alzheimer disease plaques (at protein CC level). Isoform 3 is expressed weakly in testis and at high levels in CC normal and cancerous prostate. {ECO:0000269|PubMed:10903839, CC ECO:0000269|PubMed:10987305, ECO:0000269|PubMed:11120884, CC ECO:0000269|PubMed:11668495, ECO:0000269|PubMed:16439095, CC ECO:0000269|PubMed:16805794}. CC -!- INDUCTION: Down-regulated in tumor cell lines in response to a high CC level of methylation in the 5' region. The CpG island methylation CC correlates with TMEFF2 silencing in tumor cell lines. CC {ECO:0000269|PubMed:10987305, ECO:0000269|PubMed:11120884}. CC -!- PTM: O-glycosylated; contains chondroitin sulfate glycosaminoglycans. CC {ECO:0000269|PubMed:11668495}. CC -!- PTM: A soluble form (TMEFF2-ECD) is produced by proteolytic shedding. CC This shedding can be induced by phorbol ester or pro-inflammatory CC cytokines such as TNFalpha, and is mediated by ADAM17. CC -!- SIMILARITY: Belongs to the tomoregulin family. CC {ECO:0000269|PubMed:17942404}. CC -!- SEQUENCE CAUTION: CC Sequence=BAA90820.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Mitochondrial contamination starting in position 361.; 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; AB017269; BAA87897.1; -; mRNA. DR EMBL; AF242221; AAG49451.1; -; Genomic_DNA. DR EMBL; AF242222; AAG49452.1; -; mRNA. DR EMBL; AF179274; AAD55776.2; -; mRNA. DR EMBL; DQ133599; AAZ43216.1; -; mRNA. DR EMBL; AY358907; AAQ89266.1; -; mRNA. DR EMBL; AK074507; BAC11030.1; -; mRNA. DR EMBL; CR457390; CAG33671.1; -; mRNA. DR EMBL; AK222691; BAD96411.1; -; mRNA. DR EMBL; AL157430; CAB75654.1; -; mRNA. DR EMBL; AC092644; AAY14874.1; -; Genomic_DNA. DR EMBL; AC098617; AAX88893.1; -; Genomic_DNA. DR EMBL; BC008973; AAH08973.1; -; mRNA. DR EMBL; AB004064; BAA90820.1; ALT_TERM; mRNA. DR EMBL; AF264150; AAF91397.1; -; Genomic_DNA. DR CCDS; CCDS2314.1; -. [Q9UIK5-1] DR CCDS; CCDS82547.1; -. [Q9UIK5-3] DR CCDS; CCDS82548.1; -. [Q9UIK5-2] DR PIR; T46914; T46914. DR RefSeq; NP_001292063.1; NM_001305134.2. [Q9UIK5-2] DR RefSeq; NP_001292074.1; NM_001305145.1. [Q9UIK5-3] DR RefSeq; NP_057276.2; NM_016192.3. [Q9UIK5-1] DR AlphaFoldDB; Q9UIK5; -. DR SMR; Q9UIK5; -. DR BioGRID; 117189; 12. DR FunCoup; Q9UIK5; 376. DR IntAct; Q9UIK5; 16. DR MINT; Q9UIK5; -. DR STRING; 9606.ENSP00000272771; -. DR MEROPS; I01.969; -. DR MEROPS; I01.978; -. DR GlyCosmos; Q9UIK5; 3 sites, No reported glycans. DR GlyGen; Q9UIK5; 2 sites. DR iPTMnet; Q9UIK5; -. DR PhosphoSitePlus; Q9UIK5; -. DR SwissPalm; Q9UIK5; -. DR BioMuta; TMEFF2; -. DR DMDM; 71153590; -. DR jPOST; Q9UIK5; -. DR MassIVE; Q9UIK5; -. DR PaxDb; 9606-ENSP00000272771; -. DR PeptideAtlas; Q9UIK5; -. DR ProteomicsDB; 84539; -. [Q9UIK5-1] DR ProteomicsDB; 84540; -. [Q9UIK5-2] DR ProteomicsDB; 84541; -. [Q9UIK5-3] DR Antibodypedia; 2895; 391 antibodies from 32 providers. DR DNASU; 23671; -. DR Ensembl; ENST00000272771.10; ENSP00000272771.5; ENSG00000144339.13. [Q9UIK5-1] DR Ensembl; ENST00000392314.5; ENSP00000376128.1; ENSG00000144339.13. [Q9UIK5-2] DR Ensembl; ENST00000409056.3; ENSP00000386871.3; ENSG00000144339.13. [Q9UIK5-3] DR GeneID; 23671; -. DR KEGG; hsa:23671; -. DR MANE-Select; ENST00000272771.10; ENSP00000272771.5; NM_016192.4; NP_057276.2. DR UCSC; uc002utc.4; human. [Q9UIK5-1] DR AGR; HGNC:11867; -. DR ClinPGx; PA36568; -. DR CTD; 23671; -. DR DisGeNET; 23671; -. DR GeneCards; TMEFF2; -. DR HGNC; HGNC:11867; TMEFF2. DR HPA; ENSG00000144339; Tissue enhanced (brain, prostate, seminal vesicle). DR MIM; 605734; gene. DR OpenTargets; ENSG00000144339; -. DR VEuPathDB; HostDB:ENSG00000144339; -. DR eggNOG; KOG3649; Eukaryota. DR GeneTree; ENSGT00940000156056; -. DR HOGENOM; CLU_048579_1_0_1; -. DR InParanoid; Q9UIK5; -. DR OMA; HCQGQTL; -. DR OrthoDB; 328123at2759; -. DR PAN-GO; Q9UIK5; 6 GO annotations based on evolutionary models. DR PhylomeDB; Q9UIK5; -. DR PathwayCommons; Q9UIK5; -. DR SignaLink; Q9UIK5; -. DR Agora; ENSG00000144339; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 23671; 7 hits in 1065 CRISPR screens. DR ChiTaRS; TMEFF2; human. DR GeneWiki; TMEFF2; -. DR GenomeRNAi; 23671; -. DR Pharos; Q9UIK5; Tbio. DR PRO; PR:Q9UIK5; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; Q9UIK5; protein. DR Bgee; ENSG00000144339; Expressed in middle temporal gyrus and 148 other cell types or tissues. DR GO; GO:0005576; C:extracellular region; IBA:GO_Central. DR GO; GO:0016020; C:membrane; NAS:UniProtKB. DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central. DR GO; GO:0030336; P:negative regulation of cell migration; IDA:MGI. DR GO; GO:0045720; P:negative regulation of integrin biosynthetic process; IMP:MGI. DR GO; GO:0051497; P:negative regulation of stress fiber assembly; IDA:MGI. DR GO; GO:0044319; P:wound healing, spreading of cells; IDA:MGI. DR CDD; cd00104; KAZAL_FS; 2. DR FunFam; 2.10.25.10:FF:000234; tomoregulin-2 isoform X1; 1. DR FunFam; 3.30.60.30:FF:000002; tomoregulin-2 isoform X1; 1. DR FunFam; 3.30.60.30:FF:000020; tomoregulin-2 isoform X2; 1. DR Gene3D; 3.30.60.30; -; 2. DR Gene3D; 2.10.25.10; Laminin; 1. DR InterPro; IPR000742; EGF. DR InterPro; IPR002350; Kazal_dom. DR InterPro; IPR036058; Kazal_dom_sf. DR PANTHER; PTHR21632; REGULATORY PROTEIN ZESTE; 1. DR PANTHER; PTHR21632:SF5; TOMOREGULIN-2 ISOFORM X1; 1. DR Pfam; PF07648; Kazal_2; 2. DR SMART; SM00280; KAZAL; 2. DR SUPFAM; SSF57196; EGF/Laminin; 1. DR SUPFAM; SSF100895; Kazal-type serine protease inhibitors; 2. DR PROSITE; PS00022; EGF_1; 1. DR PROSITE; PS01186; EGF_2; 1. DR PROSITE; PS50026; EGF_3; 1. DR PROSITE; PS51465; KAZAL_2; 2. PE 1: Evidence at protein level; KW Alternative splicing; Direct protein sequencing; Disulfide bond; KW EGF-like domain; Glycoprotein; Membrane; Proteoglycan; KW Proteomics identification; Reference proteome; Repeat; Secreted; Signal; KW Transmembrane; Transmembrane helix. FT SIGNAL 1..40 FT /evidence="ECO:0000269|PubMed:15340161" FT CHAIN 41..374 FT /note="Tomoregulin-2" FT /id="PRO_0000016587" FT TOPO_DOM 41..320 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 321..341 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 342..374 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 90..137 FT /note="Kazal-like 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798" FT DOMAIN 181..229 FT /note="Kazal-like 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798" FT DOMAIN 261..301 FT /note="EGF-like" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT REGION 303..320 FT /note="Required for shedding" FT /evidence="ECO:0000269|PubMed:17942404" FT REGION 353..374 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 356..374 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 97..98 FT /note="Reactive bond" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798" FT SITE 188..189 FT /note="Reactive bond" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798" FT CARBOHYD 204 FT /note="N-linked (GlcNAc...) (complex) asparagine; atypical" FT /evidence="ECO:0000269|PubMed:19139490" FT CARBOHYD 230 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 91..121 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798" FT DISULFID 95..114 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798" FT DISULFID 103..135 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798" FT DISULFID 182..213 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798" FT DISULFID 186..206 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798" FT DISULFID 195..227 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798" FT DISULFID 265..278 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 273..289 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 291..300 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT VAR_SEQ 147..175 FT /note="VHEGSGETSQKETSTCDICQFGAECDEDA -> GRSCLFTYLKIYWWILLCI FT FTYVCSISDI (in isoform 3)" FT /evidence="ECO:0000303|PubMed:16439095" FT /id="VSP_024973" FT VAR_SEQ 176..374 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:16439095" FT /id="VSP_024974" FT VAR_SEQ 344..346 FT /note="KCP -> AKL (in isoform 2)" FT /evidence="ECO:0000303|PubMed:17974005, ECO:0000303|Ref.7" FT /id="VSP_014312" FT VAR_SEQ 347..374 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:17974005, ECO:0000303|Ref.7" FT /id="VSP_014313" FT CONFLICT 28 FT /note="M -> V (in Ref. 8; BAD96411)" FT /evidence="ECO:0000305" FT CONFLICT 63 FT /note="E -> G (in Ref. 6; BAC11030)" FT /evidence="ECO:0000305" FT CONFLICT 222 FT /note="M -> T (in Ref. 8; BAD96411)" FT /evidence="ECO:0000305" FT CONFLICT 339 FT /note="L -> H (in Ref. 8; BAD96411)" FT /evidence="ECO:0000305" SQ SEQUENCE 374 AA; 41428 MW; 44452F680FEBDCDB CRC64; MVLWESPRQC SSWTLCEGFC WLLLLPVMLL IVARPVKLAA FPTSLSDCQT PTGWNCSGYD DRENDLFLCD TNTCKFDGEC LRIGDTVTCV CQFKCNNDYV PVCGSNGESY QNECYLRQAA CKQQSEILVV SEGSCATDAG SGSGDGVHEG SGETSQKETS TCDICQFGAE CDEDAEDVWC VCNIDCSQTN FNPLCASDGK SYDNACQIKE ASCQKQEKIE VMSLGRCQDN TTTTTKSEDG HYARTDYAEN ANKLEESARE HHIPCPEHYN GFCMHGKCEH SINMQEPSCR CDAGYTGQHC EKKDYSVLYV VPGPVRFQYV LIAAVIGTIQ IAVICVVVLC ITRKCPRSNR IHRQKQNTGH YSSDNTTRAS TRLI // ID TNR21_HUMAN Reviewed; 655 AA. AC O75509; B2RDI9; Q0D2P5; Q96D86; DT 27-MAY-2002, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1998, sequence version 1. DT 28-JAN-2026, entry version 210. DE RecName: Full=Tumor necrosis factor receptor superfamily member 21; DE AltName: Full=Death receptor 6; DE AltName: CD_antigen=CD358; DE Flags: Precursor; GN Name=TNFRSF21; Synonyms=DR6; ORFNames=UNQ437/PRO868; 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], FUNCTION, TISSUE SPECIFICITY, AND INTERACTION RP WITH TRADD. RX PubMed=9714541; DOI=10.1016/s0014-5793(98)00791-1; RA Pan G., Bauer J.H., Haridas V., Wang S., Liu D., Yu G., Vincenz C., RA Aggarwal B.B., Ni J., Dixit V.M.; RT "Identification and functional characterization of DR6, a novel death RT domain-containing TNF receptor."; RL FEBS Lett. 431:351-356(1998). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 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 (MAY-2003) 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 MRNA]. RC TISSUE=Brain, Colon, and 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 [7] RP SUBCELLULAR LOCATION, GLYCOSYLATION AT ASN-82; ASN-141; ASN-252; ASN-257; RP ASN-278 AND ASN-289, MUTAGENESIS OF ASN-82; ASN-141; ASN-252; ASN-257; RP ASN-278 AND ASN-289, INDUCTION BY TNF, AND PALMITOYLATION AT CYS-368. RX PubMed=19654028; DOI=10.1016/j.bbamcr.2009.07.008; RA Klima M., Zajedova J., Doubravska L., Andera L.; RT "Functional analysis of the posttranslational modifications of the death RT receptor 6."; RL Biochim. Biophys. Acta 1793:1579-1587(2009). RN [8] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=21725297; DOI=10.1038/nm.2373; RA Mi S., Lee X., Hu Y., Ji B., Shao Z., Yang W., Huang G., Walus L., RA Rhodes K., Gong B.J., Miller R.H., Pepinsky R.B.; RT "Death receptor 6 negatively regulates oligodendrocyte survival, maturation RT and myelination."; RL Nat. Med. 17:816-821(2011). RN [9] RP FUNCTION. RX PubMed=22761420; DOI=10.1074/jbc.m112.362038; RA Zeng L., Li T., Xu D.C., Liu J., Mao G., Cui M.Z., Fu X., Xu X.; RT "Death receptor 6 induces apoptosis not through type I or type II pathways, RT but via a unique mitochondria-dependent pathway by interacting with Bax RT protein."; RL J. Biol. Chem. 287:29125-29133(2012). RN [10] RP INDUCTION, TISSUE SPECIFICITY, AND INTERACTION WITH NGFR. RX PubMed=23559013; DOI=10.1038/cddis.2013.110; RA Hu Y., Lee X., Shao Z., Apicco D., Huang G., Gong B.J., Pepinsky R.B., RA Mi S.; RT "A DR6/p75(NTR) complex is responsible for beta-amyloid-induced cortical RT neuron death."; RL Cell Death Dis. 4:E579-E579(2013). RN [11] RP INTERACTION WITH HCV NON-STRUCTURAL PROTEIN 5A (MICROBIAL INFECTION). RX PubMed=28743875; DOI=10.1038/s41598-017-06740-9; RA Luong T.T.D., Tran G.V.Q., Shin D.J., Lim Y.S., Hwang S.B.; RT "Hepatitis C Virus Exploits Death Receptor 6-mediated Signaling Pathway to RT Facilitate Viral Propagation."; RL Sci. Rep. 7:6445-6445(2017). RN [12] RP FUNCTION, SUBCELLULAR LOCATION, OXIDATION, AND INTERACTION WITH CASP8. RX PubMed=34012073; DOI=10.1038/s41422-021-00506-9; RA Zhang J.Y., Zhou B., Sun R.Y., Ai Y.L., Cheng K., Li F.N., Wang B.R., RA Liu F.J., Jiang Z.H., Wang W.J., Zhou D., Chen H.Z., Wu Q.; RT "The metabolite alpha-KG induces GSDMC-dependent pyroptosis through death RT receptor 6-activated caspase-8."; RL Cell Res. 31:980-997(2021). RN [13] RP STRUCTURE BY NMR OF 562-655. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of the carboxyl-terminal CARD-like domain in human RT TNFR-related death receptor-6."; RL Submitted (DEC-2006) to the PDB data bank. RN [14] RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 42-218, AND DISULFIDE BOND. RX PubMed=21463639; DOI=10.1016/j.jmb.2011.03.048; RA Kuester M., Kemmerzehl S., Dahms S.O., Roeser D., Than M.E.; RT "The crystal structure of death receptor 6 (DR6): a potential receptor of RT the amyloid precursor protein (APP)."; RL J. Mol. Biol. 409:189-201(2011). RN [15] RP X-RAY CRYSTALLOGRAPHY (2.09 ANGSTROMS) OF 42-349, DISULFIDE BOND, AND RP GLYCOSYLATION. RX PubMed=22525750; DOI=10.1107/s0907444912004490; RA Ru H., Zhao L., Ding W., Jiao L., Shaw N., Liang W., Zhang L., Hung L.W., RA Matsugaki N., Wakatsuki S., Liu Z.J.; RT "S-SAD phasing study of death receptor 6 and its solution conformation RT revealed by SAXS."; RL Acta Crystallogr. D 68:521-530(2012). CC -!- FUNCTION: Promotes apoptosis, possibly via a pathway that involves the CC activation of NF-kappa-B. Can also promote apoptosis mediated by BAX CC and by the release of cytochrome c from the mitochondria into the CC cytoplasm. Trophic-factor deprivation triggers the cleavage of surface CC APP by beta-secretase to release sAPP-beta which is further cleaved to CC release an N-terminal fragment of APP (N-APP). Negatively regulates CC oligodendrocyte survival, maturation and myelination. Plays a role in CC signaling cascades triggered by stimulation of T-cell receptors, in the CC adaptive immune response and in the regulation of T-cell CC differentiation and proliferation. Negatively regulates T-cell CC responses and the release of cytokines such as IL4, IL5, IL10, IL13 and CC IFNG by Th2 cells. Negatively regulates the production of IgG, IgM and CC IgM in response to antigens. May inhibit the activation of JNK in CC response to T-cell stimulation. Also acts as a regulator of pyroptosis: CC recruits CASP8 in response to reactive oxygen species (ROS) and CC subsequent oxidation, leading to activation of GSDMC (PubMed:34012073). CC {ECO:0000269|PubMed:21725297, ECO:0000269|PubMed:22761420, CC ECO:0000269|PubMed:34012073, ECO:0000269|PubMed:9714541}. CC -!- SUBUNIT: Associates with TRADD (PubMed:9714541). Interacts with NGFR CC (PubMed:23559013). Interacts with CASP8 (PubMed:34012073). CC {ECO:0000269|PubMed:23559013, ECO:0000269|PubMed:34012073, CC ECO:0000269|PubMed:9714541}. CC -!- SUBUNIT: (Microbial infection) Interacts with hepatitis C virus (HCV) CC non-structural protein 5A; this interaction allows the modulation by CC the virus of JNK, p38 MAPK, STAT3, and Akt signaling pathways in a DR6- CC dependent manner. {ECO:0000269|PubMed:28743875}. CC -!- INTERACTION: CC O75509; P05067: APP; NbExp=2; IntAct=EBI-2313231, EBI-77613; CC O75509; P08138: NGFR; NbExp=4; IntAct=EBI-2313231, EBI-1387782; CC O75509; Q6UXB8: PI16; NbExp=3; IntAct=EBI-2313231, EBI-12810028; CC O75509; O43765: SGTA; NbExp=3; IntAct=EBI-2313231, EBI-347996; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:19654028}; CC Single-pass type I membrane protein {ECO:0000269|PubMed:19654028}. CC Note=Endocytosed following oxidation in response to reactive oxygen CC species (ROS). {ECO:0000269|PubMed:34012073}. CC -!- TISSUE SPECIFICITY: Detected in fetal spinal cord and in brain neurons, CC with higher levels in brain from Alzheimer disease patients (at protein CC level). Highly expressed in heart, brain, placenta, pancreas, lymph CC node, thymus and prostate. Detected at lower levels in lung, skeletal CC muscle, kidney, testis, uterus, small intestine, colon, spleen, bone CC marrow and fetal liver. Very low levels were found in adult liver and CC peripheral blood leukocytes. {ECO:0000269|PubMed:21725297, CC ECO:0000269|PubMed:23559013, ECO:0000269|PubMed:9714541}. CC -!- INDUCTION: Up-regulated by TNF. {ECO:0000269|PubMed:19654028, CC ECO:0000269|PubMed:23559013}. CC -!- PTM: Oxidized in response to reactive oxygen species (ROS), leading to CC endocytosis. {ECO:0000269|PubMed:34012073}. CC -!- CAUTION: It is uncertain whether Met-1 or Met-25 is the initiator. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH10241.1; Type=Erroneous initiation; Note=Truncated N-terminus.; 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; AF068868; AAC34583.1; -; mRNA. DR EMBL; AY358304; AAQ88671.1; -; mRNA. DR EMBL; AK315560; BAG37936.1; -; mRNA. DR EMBL; BT007420; AAP36088.1; -; mRNA. DR EMBL; AL096801; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC010241; AAH10241.1; ALT_INIT; mRNA. DR EMBL; BC017730; AAH17730.1; -; mRNA. DR EMBL; BC021572; AAH21572.1; -; mRNA. DR CCDS; CCDS4921.1; -. DR RefSeq; NP_055267.1; NM_014452.5. DR PDB; 2DBH; NMR; -; A=567-655. DR PDB; 3QO4; X-ray; 2.20 A; A=42-218. DR PDB; 3U3P; X-ray; 2.09 A; A=42-348. DR PDB; 3U3Q; X-ray; 2.70 A; A=42-348. DR PDB; 3U3S; X-ray; 2.70 A; A=42-348. DR PDB; 3U3T; X-ray; 3.21 A; A=42-348. DR PDB; 3U3V; X-ray; 2.96 A; A=42-348. DR PDBsum; 2DBH; -. DR PDBsum; 3QO4; -. DR PDBsum; 3U3P; -. DR PDBsum; 3U3Q; -. DR PDBsum; 3U3S; -. DR PDBsum; 3U3T; -. DR PDBsum; 3U3V; -. DR AlphaFoldDB; O75509; -. DR SMR; O75509; -. DR BioGRID; 118090; 34. DR CORUM; O75509; -. DR DIP; DIP-53299N; -. DR FunCoup; O75509; 896. DR IntAct; O75509; 21. DR MINT; O75509; -. DR STRING; 9606.ENSP00000296861; -. DR GlyConnect; 1981; 6 N-Linked glycans (5 sites). DR GlyCosmos; O75509; 9 sites, 7 glycans. DR GlyGen; O75509; 12 sites, 8 N-linked glycans (5 sites), 2 O-linked glycans (4 sites). DR iPTMnet; O75509; -. DR PhosphoSitePlus; O75509; -. DR SwissPalm; O75509; -. DR BioMuta; TNFRSF21; -. DR jPOST; O75509; -. DR MassIVE; O75509; -. DR PaxDb; 9606-ENSP00000296861; -. DR PeptideAtlas; O75509; -. DR ProteomicsDB; 50058; -. DR Antibodypedia; 1463; 654 antibodies from 39 providers. DR DNASU; 27242; -. DR Ensembl; ENST00000296861.2; ENSP00000296861.2; ENSG00000146072.7. DR GeneID; 27242; -. DR KEGG; hsa:27242; -. DR MANE-Select; ENST00000296861.2; ENSP00000296861.2; NM_014452.5; NP_055267.1. DR UCSC; uc003oyv.5; human. DR AGR; HGNC:13469; -. DR ClinPGx; PA37775; -. DR CTD; 27242; -. DR DisGeNET; 27242; -. DR GeneCards; TNFRSF21; -. DR HGNC; HGNC:13469; TNFRSF21. DR HPA; ENSG00000146072; Tissue enhanced (brain, urinary bladder). DR MalaCards; TNFRSF21; -. DR MIM; 605732; gene. DR OpenTargets; ENSG00000146072; -. DR VEuPathDB; HostDB:ENSG00000146072; -. DR eggNOG; ENOG502QVMX; Eukaryota. DR GeneTree; ENSGT00940000156212; -. DR HOGENOM; CLU_027496_0_0_1; -. DR InParanoid; O75509; -. DR OMA; QVGTQWI; -. DR OrthoDB; 8933063at2759; -. DR PAN-GO; O75509; 8 GO annotations based on evolutionary models. DR PhylomeDB; O75509; -. DR PathwayCommons; O75509; -. DR Reactome; R-HSA-1989781; PPARA activates gene expression. DR SignaLink; O75509; -. DR SIGNOR; O75509; -. DR Agora; ENSG00000146072; -. DR BioGRID-ORCS; 27242; 13 hits in 1157 CRISPR screens. DR ChiTaRS; TNFRSF21; human. DR EvolutionaryTrace; O75509; -. DR GeneWiki; TNFRSF21; -. DR GenomeRNAi; 27242; -. DR Pharos; O75509; Tbio. DR PRO; PR:O75509; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; O75509; protein. DR Bgee; ENSG00000146072; Expressed in islet of Langerhans and 197 other cell types or tissues. DR ExpressionAtlas; O75509; baseline and differential. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0002250; P:adaptive immune response; ISS:UniProtKB. DR GO; GO:0006915; P:apoptotic process; IMP:UniProtKB. DR GO; GO:0007413; P:axonal fasciculation; IEA:Ensembl. DR GO; GO:0001783; P:B cell apoptotic process; ISS:UniProtKB. DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IDA:UniProtKB. DR GO; GO:0006959; P:humoral immune response; ISS:UniProtKB. DR GO; GO:0042552; P:myelination; ISS:UniProtKB. DR GO; GO:0030889; P:negative regulation of B cell proliferation; ISS:UniProtKB. DR GO; GO:0032693; P:negative regulation of interleukin-10 production; ISS:UniProtKB. DR GO; GO:0032696; P:negative regulation of interleukin-13 production; ISS:UniProtKB. DR GO; GO:0032714; P:negative regulation of interleukin-5 production; ISS:UniProtKB. DR GO; GO:0031642; P:negative regulation of myelination; IMP:UniProtKB. DR GO; GO:0042130; P:negative regulation of T cell proliferation; ISS:UniProtKB. DR GO; GO:0051402; P:neuron apoptotic process; IBA:GO_Central. DR GO; GO:0097252; P:oligodendrocyte apoptotic process; ISS:UniProtKB. DR GO; GO:0048713; P:regulation of oligodendrocyte differentiation; ISS:UniProtKB. DR GO; GO:0050852; P:T cell receptor signaling pathway; ISS:UniProtKB. DR CDD; cd08778; Death_TNFRSF21; 1. DR CDD; cd10583; TNFRSF21; 1. DR FunFam; 1.10.533.10:FF:000005; Tumor necrosis factor receptor superfamily member 21; 1. DR FunFam; 2.10.50.10:FF:000010; Tumor necrosis factor receptor superfamily member 21; 1. DR FunFam; 2.10.50.10:FF:000011; Tumor necrosis factor receptor superfamily member 21; 1. DR FunFam; 1.10.533.10:FF:000009; tumor necrosis factor receptor superfamily member 21; 1. DR Gene3D; 1.10.533.10; Death Domain, Fas; 2. DR Gene3D; 2.10.50.10; Tumor Necrosis Factor Receptor, subunit A, domain 2; 2. DR InterPro; IPR011029; DEATH-like_dom_sf. DR InterPro; IPR000488; Death_dom. DR InterPro; IPR001368; TNFR/NGFR_Cys_rich_reg. DR InterPro; IPR022330; TNFR_21. DR InterPro; IPR034037; TNFRSF21_death. DR InterPro; IPR034034; TNFRSF21_N. DR PANTHER; PTHR46921; TUMOR NECROSIS FACTOR RECEPTOR SUPERFAMILY MEMBER 21; 1. DR PANTHER; PTHR46921:SF1; TUMOR NECROSIS FACTOR RECEPTOR SUPERFAMILY MEMBER 21; 1. DR Pfam; PF00531; Death; 1. DR Pfam; PF00020; TNFR_c6; 2. DR PRINTS; PR01971; TNFACTORR21. DR SMART; SM00005; DEATH; 1. DR SMART; SM01411; Ephrin_rec_like; 2. DR SMART; SM00208; TNFR; 4. DR SUPFAM; SSF47986; DEATH domain; 1. DR SUPFAM; SSF57586; TNF receptor-like; 2. DR PROSITE; PS50017; DEATH_DOMAIN; 1. DR PROSITE; PS00652; TNFR_NGFR_1; 1. DR PROSITE; PS50050; TNFR_NGFR_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Adaptive immunity; Apoptosis; Cell membrane; Disulfide bond; KW Glycoprotein; Host-virus interaction; Immunity; Lipoprotein; Membrane; KW Oxidation; Palmitate; Proteomics identification; Receptor; KW Reference proteome; Repeat; Signal; Transmembrane; Transmembrane helix. FT SIGNAL 1..41 FT /evidence="ECO:0000255" FT CHAIN 42..655 FT /note="Tumor necrosis factor receptor superfamily member FT 21" FT /id="PRO_0000034602" FT TOPO_DOM 42..349 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 350..370 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 371..655 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REPEAT 50..88 FT /note="TNFR-Cys 1" FT REPEAT 90..131 FT /note="TNFR-Cys 2" FT REPEAT 133..167 FT /note="TNFR-Cys 3" FT REPEAT 170..211 FT /note="TNFR-Cys 4" FT DOMAIN 415..498 FT /note="Death" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00064" FT REGION 243..286 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 318..337 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 243..261 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 268..282 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT LIPID 368 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:19654028" FT CARBOHYD 82 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19654028" FT CARBOHYD 141 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19654028" FT CARBOHYD 252 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19654028" FT CARBOHYD 257 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19654028" FT CARBOHYD 278 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19654028" FT CARBOHYD 289 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19654028" FT DISULFID 67..80 FT DISULFID 70..88 FT DISULFID 91..106 FT DISULFID 109..123 FT DISULFID 113..131 FT DISULFID 133..144 FT DISULFID 150..168 FT DISULFID 171..186 FT DISULFID 192..211 FT MUTAGEN 82 FT /note="N->Q: Abolishes one glycosylation site and reduces FT total N-glycosylation; when associated with Q-252; Q-278 FT and Q-289." FT /evidence="ECO:0000269|PubMed:19654028" FT MUTAGEN 141 FT /note="N->Q: Abolishes one glycosylation site and reduces FT total N-glycosylation; when associated with Q-82; Q-252; Q- FT 278 and Q-289." FT /evidence="ECO:0000269|PubMed:19654028" FT MUTAGEN 252 FT /note="N->Q: Abolishes one glycosylation site and reduces FT total N-glycosylation; when associated with Q-278 and Q- FT 289." FT /evidence="ECO:0000269|PubMed:19654028" FT MUTAGEN 257 FT /note="N->Q: Abolishes one glycosylation site and reduces FT total N-glycosylation; when associated with Q-82; Q-141; Q- FT 252; Q-278 and Q-289." FT /evidence="ECO:0000269|PubMed:19654028" FT MUTAGEN 278 FT /note="N->Q: Abolishes one glycosylation site and reduces FT total N-glycosylation. Abolishes one glycosylation site and FT reduces total N-glycosylation; when associated with Q-82; FT Q-141; Q-252; Q-257 and Q-289." FT /evidence="ECO:0000269|PubMed:19654028" FT MUTAGEN 289 FT /note="N->Q: Abolishes one glycosylation site and reduces FT total N-glycosylation; when associated with Q-278." FT /evidence="ECO:0000269|PubMed:19654028" FT MUTAGEN 368 FT /note="C->V: Abolishes palmitoylation." FT STRAND 53..57 FT /evidence="ECO:0007829|PDB:3U3P" FT TURN 59..61 FT /evidence="ECO:0007829|PDB:3U3P" FT STRAND 64..68 FT /evidence="ECO:0007829|PDB:3U3P" FT STRAND 74..78 FT /evidence="ECO:0007829|PDB:3U3P" FT STRAND 82..84 FT /evidence="ECO:0007829|PDB:3U3T" FT STRAND 87..90 FT /evidence="ECO:0007829|PDB:3U3P" FT STRAND 99..101 FT /evidence="ECO:0007829|PDB:3U3V" FT STRAND 118..121 FT /evidence="ECO:0007829|PDB:3U3P" FT STRAND 130..132 FT /evidence="ECO:0007829|PDB:3U3P" FT STRAND 137..140 FT /evidence="ECO:0007829|PDB:3U3P" FT STRAND 143..146 FT /evidence="ECO:0007829|PDB:3U3P" FT STRAND 154..158 FT /evidence="ECO:0007829|PDB:3U3P" FT STRAND 162..164 FT /evidence="ECO:0007829|PDB:3U3P" FT STRAND 167..170 FT /evidence="ECO:0007829|PDB:3U3P" FT STRAND 181..183 FT /evidence="ECO:0007829|PDB:3U3P" FT HELIX 193..195 FT /evidence="ECO:0007829|PDB:3U3P" FT STRAND 198..201 FT /evidence="ECO:0007829|PDB:3U3P" FT STRAND 205..207 FT /evidence="ECO:0007829|PDB:3U3P" FT STRAND 210..212 FT /evidence="ECO:0007829|PDB:3U3P" FT STRAND 571..573 FT /evidence="ECO:0007829|PDB:2DBH" FT HELIX 579..591 FT /evidence="ECO:0007829|PDB:2DBH" FT HELIX 598..606 FT /evidence="ECO:0007829|PDB:2DBH" FT HELIX 609..616 FT /evidence="ECO:0007829|PDB:2DBH" FT HELIX 621..635 FT /evidence="ECO:0007829|PDB:2DBH" FT HELIX 637..650 FT /evidence="ECO:0007829|PDB:2DBH" FT HELIX 652..654 FT /evidence="ECO:0007829|PDB:2DBH" SQ SEQUENCE 655 AA; 71845 MW; 48939391C4852A33 CRC64; MGTSPSSSTA LASCSRIARR ATATMIAGSL LLLGFLSTTT AQPEQKASNL IGTYRHVDRA TGQVLTCDKC PAGTYVSEHC TNTSLRVCSS CPVGTFTRHE NGIEKCHDCS QPCPWPMIEK LPCAALTDRE CTCPPGMFQS NATCAPHTVC PVGWGVRKKG TETEDVRCKQ CARGTFSDVP SSVMKCKAYT DCLSQNLVVI KPGTKETDNV CGTLPSFSSS TSPSPGTAIF PRPEHMETHE VPSSTYVPKG MNSTESNSSA SVRPKVLSSI QEGTVPDNTS SARGKEDVNK TLPNLQVVNH QQGPHHRHIL KLLPSMEATG GEKSSTPIKG PKRGHPRQNL HKHFDINEHL PWMIVLFLLL VLVVIVVCSI RKSSRTLKKG PRQDPSAIVE KAGLKKSMTP TQNREKWIYY CNGHGIDILK LVAAQVGSQW KDIYQFLCNA SEREVAAFSN GYTADHERAY AALQHWTIRG PEASLAQLIS ALRQHRRNDV VEKIRGLMED TTQLETDKLA LPMSPSPLSP SPIPSPNAKL ENSALLTVEP SPQDKNKGFF VDESEPLLRC DSTSSGSSAL SRNGSFITKE KKDTVLRQVR LDPCDLQPIF DDMLHFLNPE ELRVIEEIPQ AEDKLDRLFE IIGVKSQEAS QTLLDSVYSH LPDLL //