ID IF4G1_HUMAN Reviewed; 1599 AA. AC Q04637; D3DNT2; D3DNT4; D3DNT5; E9PFM1; G5E9S1; O43177; O95066; Q5HYG0; AC Q6ZN21; Q8N102; DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot. DT 20-APR-2010, sequence version 4. DT 28-JAN-2026, entry version 251. DE RecName: Full=Eukaryotic translation initiation factor 4 gamma 1; DE Short=eIF-4-gamma 1; DE Short=eIF-4G 1; DE Short=eIF-4G1; DE AltName: Full=p220; GN Name=EIF4G1; Synonyms=EIF4F, EIF4G, EIF4GI; 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 7), AND VARIANT VAL-432. RC TISSUE=Brain; RX PubMed=1429670; DOI=10.1016/s0021-9258(18)50080-6; RA Yan R., Rychlik W., Etchison D., Rhoads R.E.; RT "Amino acid sequence of the human protein synthesis initiation factor eIF-4 RT gamma."; RL J. Biol. Chem. 267:23226-23231(1992). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B), AND INTERACTION WITH PABPC1. RX PubMed=9857202; DOI=10.1093/emboj/17.24.7480; RA Imataka H., Gradi A., Sonenberg N.; RT "A newly identified N-terminal amino acid sequence of human eIF4G binds RT poly(A)-binding protein and functions in poly(A)-dependent translation."; RL EMBO J. 17:7480-7489(1998). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM C). RX PubMed=9418880; DOI=10.1128/mcb.18.1.334; RA Gradi A., Imataka H., Svitkin Y.V., Rom E., Raught B., Morino S., RA Sonenberg N.; RT "A novel functional human eukaryotic translation initiation factor 4G."; RL Mol. Cell. Biol. 18:334-342(1998). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 8), VARIANTS ALA-161 AND VAL-432, AND RP ALTERNATIVE INITIATION. RX PubMed=12052860; DOI=10.1128/mcb.22.13.4499-4511.2002; RA Byrd M.P., Zamora M., Lloyd R.E.; RT "Generation of multiple isoforms of eukaryotic translation initiation RT factor 4GI by use of alternate translation initiation codons."; RL Mol. Cell. Biol. 22:4499-4511(2002). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A). 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 MRNA] (ISOFORM A), AND VARIANT ALA-161. RC TISSUE=Endometrial tumor; 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 [7] 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 [8] 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 [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 30-206, NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF RP 180-234, VARIANT ALA-161, AND INTERACTION WITH ROTAVIRAL NSP3. RX PubMed=9755181; DOI=10.1093/emboj/17.19.5811; RA Piron M., Vende P., Cohen J., Poncet D.; RT "Rotavirus RNA binding protein NSP3, interacts with eIF-4GI and evicts the RT poly(A) binding protein from eIF4F."; RL EMBO J. 17:5811-5821(1998). RN [10] RP NUCLEOTIDE SEQUENCE [MRNA] OF 37-1599 (ISOFORM 8), INTERACTION WITH EIF4A, RP VARIANTS ALA-161 AND VAL-432, AND MUTAGENESIS OF LEU-768; LEU-771; PHE-776; RP 842-LEU-LEU-843; 851-PHE-GLU-852; LEU-896; ILE-902; LEU-905; ARG-974; RP PHE-977; LEU-985 AND TRP-990. RX PubMed=9372926; DOI=10.1128/mcb.17.12.6940; RA Imataka H., Sonenberg N.; RT "Human eukaryotic translation initiation factor 4G (eIF4G) possesses two RT separate and independent binding sites for eIF4A."; RL Mol. Cell. Biol. 17:6940-6947(1997). RN [11] RP NUCLEOTIDE SEQUENCE [MRNA] OF 605-721, INTERACTION WITH EIF4E, AND RP MUTAGENESIS OF TYR-612 AND 617-LEU-LEU-618. RX PubMed=7651417; DOI=10.1128/mcb.15.9.4990; RA Mader S., Lee H., Pause A., Sonenberg N.; RT "The translation initiation factor eIF-4E binds to a common motif shared by RT the translation factor eIF-4 gamma and the translational repressors 4E- RT binding proteins."; RL Mol. Cell. Biol. 15:4990-4997(1995). RN [12] RP NUCLEOTIDE SEQUENCE [MRNA] OF 682-912 (ISOFORM 8). RA De Gregorio E.; RL Submitted (AUG-1997) to the EMBL/GenBank/DDBJ databases. RN [13] RP CLEAVAGE BY RHINOVIRUS AND COXSACKIEVIRUS PROTEASE. RX PubMed=8396129; DOI=10.1016/s0021-9258(19)36499-3; RA Lamphear B.J., Yan R., Yang F., Waters D., Liebig H.-D., Klump H., RA Kuechler E., Skern T., Rhoads R.E.; RT "Mapping the cleavage site in protein synthesis initiation factor eIF-4 RT gamma of the 2A proteases from human Coxsackievirus and rhinovirus."; RL J. Biol. Chem. 268:19200-19203(1993). RN [14] RP INTERACTION WITH EIF4E. RC TISSUE=Placenta; RX PubMed=7935836; DOI=10.1038/371762a0; RA Pause A., Belsham G.J., Gingras A.-C., Donze O., Lin T.-A., RA Lawrence J.C. Jr., Sonenberg N.; RT "Insulin-dependent stimulation of protein synthesis by phosphorylation of a RT regulator of 5'-cap function."; RL Nature 371:762-767(1994). RN [15] RP INTERACTION WITH EIF4E AND EIF4EBP1. RX PubMed=8521827; DOI=10.1002/j.1460-2075.1995.tb00257.x; RA Haghighat A., Mader S., Pause A., Sonenberg N.; RT "Repression of cap-dependent translation by 4E-binding protein 1: RT competition with p220 for binding to eukaryotic initiation factor-4E."; RL EMBO J. 14:5701-5709(1995). RN [16] RP MUTAGENESIS OF GLY-682. RX PubMed=8961935; DOI=10.1021/bi961864t; RA Lamphear B.J., Rhoads R.E.; RT "A single amino acid change in protein synthesis initiation factor 4G RT renders cap-dependent translation resistant to picornaviral 2A proteases."; RL Biochemistry 35:15726-15733(1996). RN [17] RP CLEAVAGE BY POLIOVIRUS. RX PubMed=9755863; DOI=10.1016/s0014-5793(98)01027-8; RA Ventoso I., MacMillan S.E., Hershey J.W., Carrasco L.; RT "Poliovirus 2A proteinase cleaves directly the eIF-4G subunit of eIF-4F RT complex."; RL FEBS Lett. 435:79-83(1998). RN [18] RP REVIEW. RX PubMed=10872469; DOI=10.1146/annurev.biochem.68.1.913; RA Gingras A.-C., Raught B., Sonenberg N.; RT "eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and RT regulators of translation."; RL Annu. Rev. Biochem. 68:913-963(1999). RN [19] RP INTERACTION WITH MKNK1. RX PubMed=9878069; DOI=10.1093/emboj/18.1.270; RA Pyronnet S., Imataka H., Gingras A.-C., Fukunaga R., Hunter T., RA Sonenberg N.; RT "Human eukaryotic translation initiation factor 4G (eIF4G) recruits mnk1 to RT phosphorylate eIF4E."; RL EMBO J. 18:270-279(1999). RN [20] RP INTERACTION WITH PABPC1, AND MUTAGENESIS OF 174-LYS--LYS-178 AND RP 184-ASP--GLN-197. RX PubMed=10996799; DOI=10.1016/s0960-9822(00)00701-6; RA Wakiyama M., Imataka H., Sonenberg N.; RT "Interaction of eIF4G with poly(A)-binding protein stimulates translation RT and is critical for Xenopus oocyte maturation."; RL Curr. Biol. 10:1147-1150(2000). RN [21] RP INTERACTION WITH PABPC1. RX PubMed=10970864; DOI=10.1093/emboj/19.17.4723; RA Gray N.K., Coller J.M., Dickson K.S., Wickens M.; RT "Multiple portions of poly(A)-binding protein stimulate translation in RT vivo."; RL EMBO J. 19:4723-4733(2000). RN [22] RP CLEAVAGE BY FMDV AND HRV-2. RX PubMed=11034318; DOI=10.1016/s0014-5793(00)01928-1; RA Glaser W., Skern T.; RT "Extremely efficient cleavage of eIF4G by picornaviral proteinases L and 2A RT in vitro."; RL FEBS Lett. 480:151-155(2000). RN [23] RP INTERACTION WITH MKNK2. RX PubMed=11154262; DOI=10.1128/mcb.21.3.743-754.2001; RA Scheper G.C., Morrice N.A., Kleijn M., Proud C.G.; RT "The mitogen-activated protein kinase signal-integrating kinase Mnk2 is a RT eukaryotic initiation factor 4E kinase with high levels of basal activity RT in mammalian cells."; RL Mol. Cell. Biol. 21:743-754(2001). RN [24] RP INTERACTION WITH HADV5 100K PROTEIN (MICROBIAL INFECTION). RX PubMed=15314025; DOI=10.1101/gad.1212504; RA Xi Q., Cuesta R., Schneider R.J.; RT "Tethering of eIF4G to adenoviral mRNAs by viral 100k protein drives RT ribosome shunting."; RL Genes Dev. 18:1997-2009(2004). RN [25] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1231, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [26] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1231, 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 [27] RP INTERACTION WITH CIRBP. RX PubMed=16513844; DOI=10.1093/nar/gkj519; RA Yang R., Weber D.J., Carrier F.; RT "Post-transcriptional regulation of thioredoxin by the stress inducible RT heterogeneous ribonucleoprotein A18."; RL Nucleic Acids Res. 34:1224-1236(2006). RN [28] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1092, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17924679; DOI=10.1021/pr070152u; RA Yu L.R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D.; RT "Improved titanium dioxide enrichment of phosphopeptides from HeLa cells RT and high confident phosphopeptide identification by cross-validation of RT MS/MS and MS/MS/MS spectra."; RL J. Proteome Res. 6:4150-4162(2007). RN [29] RP INTERACTION WITH RBM4. RX PubMed=17284590; DOI=10.1073/pnas.0611015104; RA Lin J.C., Hsu M., Tarn W.Y.; RT "Cell stress modulates the function of splicing regulatory protein RBM4 in RT translation control."; RL Proc. Natl. Acad. Sci. U.S.A. 104:2235-2240(2007). RN [30] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Platelet; RX PubMed=18088087; DOI=10.1021/pr0704130; RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J., RA Schuetz C., Walter U., Gambaryan S., Sickmann A.; RT "Phosphoproteome of resting human platelets."; RL J. Proteome Res. 7:526-534(2008). RN [31] RP INTERACTION WITH ROTAVIRUS A NSP3 (MICROBIAL INFECTION). RX PubMed=18799579; DOI=10.1128/jvi.00872-08; RA Harb M., Becker M.M., Vitour D., Baron C.H., Vende P., Brown S.C., RA Bolte S., Arold S.T., Poncet D.; RT "Nuclear localization of cytoplasmic poly(A)-binding protein upon rotavirus RT infection involves the interaction of NSP3 with eIF4G and RoXaN."; RL J. Virol. 82:11283-11293(2008). RN [32] RP INTERACTION WITH DAZAP2, AND SUBCELLULAR LOCATION. RX PubMed=17984221; DOI=10.1128/mcb.01226-07; RA Kim J.E., Ryu I., Kim W.J., Song O.K., Ryu J., Kwon M.Y., Kim J.H., RA Jang S.K.; RT "Proline-rich transcript in brain protein induces stress granule RT formation."; RL Mol. Cell. Biol. 28:803-813(2008). RN [33] RP INTERACTION WITH MIF4GD. RX PubMed=18025107; DOI=10.1128/mcb.01500-07; RA Cakmakci N.G., Lerner R.S., Wagner E.J., Zheng L., Marzluff W.F.; RT "SLIP1, a factor required for activation of histone mRNA translation by the RT stem-loop binding protein."; RL Mol. Cell. Biol. 28:1182-1194(2008). RN [34] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-207; THR-223; THR-647; RP SER-1092 AND SER-1209, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [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 ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-1095, AND IDENTIFICATION BY MASS RP 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 [38] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1028; SER-1092; SER-1185; RP SER-1187; SER-1209; THR-1211; SER-1231 AND SER-1596, 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 [39] 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 [40] RP PHOSPHORYLATION AT SER-1185. RX PubMed=21576361; DOI=10.1128/mcb.05589-11; RA Dobrikov M., Dobrikova E., Shveygert M., Gromeier M.; RT "Phosphorylation of eukaryotic translation initiation factor 4G1 (eIF4G1) RT by protein kinase C{alpha} regulates eIF4G1 binding to Mnk1."; RL Mol. Cell. Biol. 31:2947-2959(2011). RN [41] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1028; SER-1092; SER-1145; RP SER-1147; SER-1185; SER-1187; SER-1209; THR-1211; SER-1231 AND SER-1596, RP AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [42] RP INTERACTION WITH DDX3X, AND SUBCELLULAR LOCATION. RX PubMed=22872150; DOI=10.1038/emboj.2012.220; RA Soto-Rifo R., Rubilar P.S., Limousin T., de Breyne S., Decimo D., RA Ohlmann T.; RT "DEAD-box protein DDX3 associates with eIF4F to promote translation of RT selected mRNAs."; RL EMBO J. 31:3745-3756(2012). RN [43] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-2 (ISOFORM C), CLEAVAGE OF RP INITIATOR METHIONINE [LARGE SCALE ANALYSIS] (ISOFORM C), AND IDENTIFICATION RP 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 [44] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-207; THR-647; SER-1028; RP SER-1077; SER-1092; SER-1145; SER-1147; SER-1185; SER-1187; SER-1194; RP SER-1209; SER-1231; SER-1238 AND SER-1596, PHOSPHORYLATION [LARGE SCALE RP ANALYSIS] AT SER-509 (ISOFORM 7), PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT RP SER-705 (ISOFORM 8), AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [45] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-314, AND IDENTIFICATION BY RP 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 [46] RP METHYLATION [LARGE SCALE ANALYSIS] AT ARG-73; ARG-110; ARG-685; ARG-694; RP ARG-1032 AND ARG-1042, METHYLATION [LARGE SCALE ANALYSIS] AT ARG-489 AND RP ARG-498 (ISOFORM 7), METHYLATION [LARGE SCALE ANALYSIS] AT ARG-685 AND RP ARG-694 (ISOFORM 8), AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Colon carcinoma; RX PubMed=24129315; DOI=10.1074/mcp.o113.027870; RA Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M., RA Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V., RA Bedford M.T., Comb M.J.; RT "Immunoaffinity enrichment and mass spectrometry analysis of protein RT methylation."; RL Mol. Cell. Proteomics 13:372-387(2014). RN [47] RP INTERACTION WITH HNRNPD, AND RNA-BINDING. RX PubMed=24423872; DOI=10.1093/nar/gkt1379; RA Lee K.H., Kim S.H., Kim H.J., Kim W., Lee H.R., Jung Y., Choi J.H., RA Hong K.Y., Jang S.K., Kim K.T.; RT "AUF1 contributes to Cryptochrome1 mRNA degradation and rhythmic RT translation."; RL Nucleic Acids Res. 42:3590-3606(2014). RN [48] RP FUNCTION. RX PubMed=29062139; DOI=10.1038/s41598-017-14262-7; RA Adjibade P., Grenier St-Sauveur V., Bergeman J., Huot M.E., Khandjian E.W., RA Mazroui R.; RT "DDX3 regulates endoplasmic reticulum stress-induced ATF4 expression."; RL Sci. Rep. 7:13832-13832(2017). RN [49] RP FUNCTION, AND INTERACTION WITH EIF1 AND EIF4E. RX PubMed=29987188; DOI=10.1128/mcb.00139-18; RA Haimov O., Sehrawat U., Tamarkin-Ben Harush A., Bahat A., Uzonyi A., RA Will A., Hiraishi H., Asano K., Dikstein R.; RT "Dynamic interaction of eukaryotic initiation factor 4G1 (eIF4G1) with RT eIF4E and eIF1 underlies scanning-dependent and -independent translation."; RL Mol. Cell. Biol. 38:0-0(2018). RN [50] RP INTERACTION WITH HUMAN NOROVIRUS VIRAL GENOME-LINKED PROTEIN (MICROBIAL RP INFECTION). RX PubMed=31403400; DOI=10.7554/elife.46681; RA Hosmillo M., Lu J., McAllaster M.R., Eaglesham J.B., Wang X., Emmott E., RA Domingues P., Chaudhry Y., Fitzmaurice T.J., Tung M.K., Panas M.D., RA McInerney G., Locker N., Wilen C.B., Goodfellow I.G.; RT "Noroviruses subvert the core stress granule component G3BP1 to promote RT viral VPg-dependent translation."; RL Elife 8:0-0(2019). RN [51] RP VARIANT [LARGE SCALE ANALYSIS] VAL-432, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [52] RP VARIANT HIS-201. RX PubMed=26740508; DOI=10.1136/jmedgenet-2015-103568; RA Lopes F., Barbosa M., Ameur A., Soares G., de Sa J., Dias A.I., RA Oliveira G., Cabral P., Temudo T., Calado E., Cruz I.F., Vieira J.P., RA Oliveira R., Esteves S., Sauer S., Jonasson I., Syvaenen A.C., RA Gyllensten U., Pinto D., Maciel P.; RT "Identification of novel genetic causes of Rett syndrome-like phenotypes."; RL J. Med. Genet. 53:190-199(2016). RN [53] RP X-RAY CRYSTALLOGRAPHY (2.38 ANGSTROMS) OF 172-199 IN COMPLEX WITH ROTAVIRAL RP NSP3, INTERACTION WITH PABPC1, AND MUTAGENESIS OF ILE-180; ILE-182; ILE-192 RP AND ILE-196. RX PubMed=12086624; DOI=10.1016/s1097-2765(02)00555-5; RA Groft C.M., Burley S.K.; RT "Recognition of eIF4G by rotavirus NSP3 reveals a basis for mRNA RT circularization."; RL Mol. Cell 9:1273-1283(2002). RN [54] RP X-RAY CRYSTALLOGRAPHY (2.24 ANGSTROMS) OF 1234-1571. RX PubMed=16698552; DOI=10.1016/j.str.2006.03.012; RA Bellsolell L., Cho-Park P.F., Poulin F., Sonenberg N., Burley S.K.; RT "Two structurally atypical HEAT domains in the C-terminal portion of human RT eIF4G support binding to eIF4A and Mnk1."; RL Structure 14:913-923(2006). RN [55] RP VARIANT [LARGE SCALE ANALYSIS] LEU-696. 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 [56] RP VARIANTS PARK18 VAL-502 AND HIS-1205, AND VARIANTS SER-71; ALA-161; RP CYS-311; VAL-432; 466-GLY--ALA-468 DEL; CYS-686; VAL-806; SER-829; RP ARG-1164; TRP-1197; ALA-1229; PRO-1233 AND SER-1257. RX PubMed=21907011; DOI=10.1016/j.ajhg.2011.08.009; RA Chartier-Harlin M.C., Dachsel J.C., Vilarino-Guell C., Lincoln S.J., RA Lepretre F., Hulihan M.M., Kachergus J., Milnerwood A.J., Tapia L., RA Song M.S., Le Rhun E., Mutez E., Larvor L., Duflot A., RA Vanbesien-Mailliot C., Kreisler A., Ross O.A., Nishioka K., RA Soto-Ortolaza A.I., Cobb S.A., Melrose H.L., Behrouz B., Keeling B.H., RA Bacon J.A., Hentati E., Williams L., Yanagiya A., Sonenberg N., RA Lockhart P.J., Zubair A.C., Uitti R.J., Aasly J.O., Krygowska-Wajs A., RA Opala G., Wszolek Z.K., Frigerio R., Maraganore D.M., Gosal D., Lynch T., RA Hutchinson M., Bentivoglio A.R., Valente E.M., Nichols W.C., Pankratz N., RA Foroud T., Gibson R.A., Hentati F., Dickson D.W., Destee A., Farrer M.J.; RT "Translation initiator EIF4G1 mutations in familial Parkinson disease."; RL Am. J. Hum. Genet. 89:398-406(2011). CC -!- FUNCTION: Component of the protein complex eIF4F, which is involved in CC the recognition of the mRNA cap, ATP-dependent unwinding of 5'-terminal CC secondary structure and recruitment of mRNA to the ribosome CC (PubMed:29987188). Exists in two complexes, either with EIF1 or with CC EIF4E (mutually exclusive) (PubMed:29987188). Together with EIF1, is CC required for leaky scanning, in particular for avoiding cap-proximal CC start codon (PubMed:29987188). Together with EIF4E, antagonizes the CC scanning promoted by EIF1-EIF4G1 and locates the start codon (through a CC TISU element) without scanning (PubMed:29987188). As a member of the CC eIF4F complex, required for endoplasmic reticulum stress-induced ATF4 CC mRNA translation (PubMed:29062139). {ECO:0000269|PubMed:29062139, CC ECO:0000269|PubMed:29987188}. CC -!- SUBUNIT: eIF4F is a multi-subunit complex, the composition of which CC varies with external and internal environmental conditions. It is CC composed of at least EIF4A, EIF4E (cap-binding) and EIF4G1/EIF4G3 CC (PubMed:7651417, PubMed:7935836, PubMed:9372926). Interacts with eIF3 CC complex, mutually exclusive with EIF4A1 or EIF4A2, EIF4E and through CC its N-terminus with PABPC1 (PubMed:10970864, PubMed:10996799, CC PubMed:12086624, PubMed:16698552, PubMed:7651417, PubMed:7935836, CC PubMed:9372926, PubMed:9857202). Interacts with EIF4E or with EIF1 CC (mutually exclusive) through a common binding site (PubMed:29987188). CC Interacts through its C-terminus with the serine/threonine kinases CC MKNK1, and with MKNK2 (PubMed:11154262, PubMed:9878069). Appears to act CC as a scaffold protein, holding these enzymes in place to phosphorylate CC EIF4E (PubMed:11154262, PubMed:9878069). Non-phosphorylated EIF4EBP1 CC competes with EIF4G1/EIF4G3 to interact with EIF4E; insulin stimulated CC MAP-kinase (MAPK1 and MAPK3) phosphorylation of EIF4EBP1 causes CC dissociation of the complex allowing EIF4G1/EIF4G3 to bind and CC consequent initiation of translation (PubMed:8521827). EIF4G1/EIF4G3 CC interacts with PABPC1 to bring about circularization of the mRNA CC (PubMed:10970864, PubMed:10996799, PubMed:12086624, PubMed:9857202). CC Interacts with EIF4E3 (By similarity). Interacts with CIRBP and MIF4GD CC (PubMed:10970864, PubMed:10996799, PubMed:16513844, PubMed:18025107). CC Interacts with RBM4 (PubMed:17284590). Interacts with HNRNPD/AUF1; the CC interaction requires RNA (PubMed:24423872). Interacts with DDX3X; the CC interaction requires RNA (PubMed:22872150). Interacts with DAZAP2 CC (PubMed:17984221). {ECO:0000250|UniProtKB:Q6NZJ6, CC ECO:0000269|PubMed:10970864, ECO:0000269|PubMed:10996799, CC ECO:0000269|PubMed:11154262, ECO:0000269|PubMed:12086624, CC ECO:0000269|PubMed:16513844, ECO:0000269|PubMed:17284590, CC ECO:0000269|PubMed:17984221, ECO:0000269|PubMed:18025107, CC ECO:0000269|PubMed:22872150, ECO:0000269|PubMed:24423872, CC ECO:0000269|PubMed:29987188, ECO:0000269|PubMed:7651417, CC ECO:0000269|PubMed:7935836, ECO:0000269|PubMed:8521827, CC ECO:0000269|PubMed:9372926, ECO:0000269|PubMed:9857202, CC ECO:0000269|PubMed:9878069}. CC -!- SUBUNIT: (Microbial infection) Interacts with rotavirus A NSP3; in this CC interaction, NSP3 takes the place of PABPC1 thereby inducing shutoff of CC host protein synthesis. {ECO:0000269|PubMed:18799579, CC ECO:0000269|PubMed:9755181}. CC -!- SUBUNIT: (Microbial infection) Interacts with human adenovirus 5 CC protein 100K; this interaction promotes translational shunt in presence CC of polysomes containing viral tripartite leader mRNAs. CC {ECO:0000269|PubMed:15314025}. CC -!- SUBUNIT: (Microbial infection) Interacts with viral genome-linked CC protein (via c-terminus); this interaction plays a role in the CC translation of viral proteins. {ECO:0000269|PubMed:31403400}. CC -!- INTERACTION: CC Q04637; O00571: DDX3X; NbExp=3; IntAct=EBI-73711, EBI-353779; CC Q04637; P55884: EIF3B; NbExp=2; IntAct=EBI-73711, EBI-366696; CC Q04637; O75822: EIF3J; NbExp=2; IntAct=EBI-73711, EBI-366647; CC Q04637; P60842: EIF4A1; NbExp=18; IntAct=EBI-73711, EBI-73449; CC Q04637; Q14240: EIF4A2; NbExp=4; IntAct=EBI-73711, EBI-73473; CC Q04637; P06730: EIF4E; NbExp=15; IntAct=EBI-73711, EBI-73440; CC Q04637; Q14103-4: HNRNPD; NbExp=3; IntAct=EBI-73711, EBI-432545; CC Q04637; Q9BUB5: MKNK1; NbExp=3; IntAct=EBI-73711, EBI-73837; CC Q04637; P11940: PABPC1; NbExp=6; IntAct=EBI-73711, EBI-81531; CC Q04637; Q9BWF3-1: RBM4; NbExp=4; IntAct=EBI-73711, EBI-15621561; CC Q04637; Q9UGR2: ZC3H7B; NbExp=3; IntAct=EBI-73711, EBI-948845; CC Q04637; Q9J0X9: UL54; Xeno; NbExp=3; IntAct=EBI-73711, EBI-7967856; CC Q04637-1; P60842: EIF4A1; NbExp=2; IntAct=EBI-5456295, EBI-73449; CC Q04637-9; Q9NQ94: A1CF; NbExp=3; IntAct=EBI-12012124, EBI-2809489; CC Q04637-9; Q8N5M1: ATPAF2; NbExp=3; IntAct=EBI-12012124, EBI-1166928; CC Q04637-9; Q2TAC2-2: CCDC57; NbExp=3; IntAct=EBI-12012124, EBI-10961624; CC Q04637-9; P55273: CDKN2D; NbExp=3; IntAct=EBI-12012124, EBI-745859; CC Q04637-9; Q99828: CIB1; NbExp=7; IntAct=EBI-12012124, EBI-372594; CC Q04637-9; P56545-3: CTBP2; NbExp=3; IntAct=EBI-12012124, EBI-10171902; CC Q04637-9; Q86UW9: DTX2; NbExp=3; IntAct=EBI-12012124, EBI-740376; CC Q04637-9; Q9H0I2: ENKD1; NbExp=3; IntAct=EBI-12012124, EBI-744099; CC Q04637-9; P51116: FXR2; NbExp=3; IntAct=EBI-12012124, EBI-740459; CC Q04637-9; Q15323: KRT31; NbExp=3; IntAct=EBI-12012124, EBI-948001; CC Q04637-9; O76011: KRT34; NbExp=3; IntAct=EBI-12012124, EBI-1047093; CC Q04637-9; Q96HA8: NTAQ1; NbExp=3; IntAct=EBI-12012124, EBI-741158; CC Q04637-9; Q9UBV8: PEF1; NbExp=3; IntAct=EBI-12012124, EBI-724639; CC Q04637-9; Q96GM5: SMARCD1; NbExp=3; IntAct=EBI-12012124, EBI-358489; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:17984221}. Nucleus CC {ECO:0000269|PubMed:17984221}. Cytoplasm, Stress granule CC {ECO:0000269|PubMed:22872150}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing, Alternative initiation; Named isoforms=8; CC Name=A; CC IsoId=Q04637-1; Sequence=Displayed; CC Name=B; CC IsoId=Q04637-3; Sequence=VSP_018720; CC Name=C; CC IsoId=Q04637-4; Sequence=VSP_018721; CC Name=D; CC IsoId=Q04637-5; Sequence=VSP_018722; CC Name=E; CC IsoId=Q04637-6; Sequence=VSP_018723; CC Name=7; CC IsoId=Q04637-7; Sequence=VSP_018723, VSP_047397; CC Name=8; CC IsoId=Q04637-8; Sequence=VSP_047397; CC Name=9; CC IsoId=Q04637-9; Sequence=VSP_047396; CC -!- PTM: Phosphorylated at multiple sites in vivo. Phosphorylation at Ser- CC 1185 by PRKCA induces binding to MKNK1. {ECO:0000269|PubMed:21576361}. CC -!- PTM: Following infection by certain enteroviruses, rhinoviruses and CC aphthoviruses, EIF4G1 is cleaved by the viral protease 2A, or the CC leader protease in the case of aphthoviruses. This shuts down the CC capped cellular mRNA transcription. {ECO:0000269|PubMed:11034318, CC ECO:0000269|PubMed:8396129, ECO:0000269|PubMed:9755863}. CC -!- DISEASE: Parkinson disease 18 (PARK18) [MIM:614251]: An autosomal CC dominant, late-onset form of Parkinson disease. Parkinson disease is a CC complex neurodegenerative disorder characterized by bradykinesia, CC resting tremor, muscular rigidity and postural instability, as well as CC by a clinically significant response to treatment with levodopa. The CC pathology involves the loss of dopaminergic neurons in the substantia CC nigra and the presence of Lewy bodies (intraneuronal accumulations of CC aggregated proteins), in surviving neurons in various areas of the CC brain. {ECO:0000269|PubMed:21907011}. Note=The disease is caused by CC variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform B]: Produced by alternative initiation at Met- CC 41 of isoform A. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform C]: Produced by alternative initiation at Met- CC 88 of isoform A. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform D]: Produced by alternative initiation at Met- CC 165 of isoform A. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform E]: Produced by alternative initiation at Met- CC 197 of isoform A. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 7]: Produced by alternative splicing. CC {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 8]: Produced by alternative splicing. CC {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 9]: Produced by alternative splicing. CC {ECO:0000305}. CC -!- SIMILARITY: Belongs to the eukaryotic initiation factor 4G family. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAC78444.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAC82471.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAA02185.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=BAD18554.1; Type=Miscellaneous discrepancy; Note=Aberrant splicing.; 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; D12686; BAA02185.1; ALT_FRAME; mRNA. DR EMBL; AY082886; AAL92872.1; -; mRNA. DR EMBL; AF281070; AAM69365.1; -; mRNA. DR EMBL; AK131407; BAD18554.1; ALT_SEQ; mRNA. DR EMBL; BX647812; CAI46013.1; -; mRNA. DR EMBL; AC078797; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471052; EAW78257.1; -; Genomic_DNA. DR EMBL; CH471052; EAW78259.1; -; Genomic_DNA. DR EMBL; CH471052; EAW78262.1; -; Genomic_DNA. DR EMBL; CH471052; EAW78263.1; -; Genomic_DNA. DR EMBL; CH471052; EAW78264.1; -; Genomic_DNA. DR EMBL; CH471052; EAW78265.1; -; Genomic_DNA. DR EMBL; CH471052; EAW78266.1; -; Genomic_DNA. DR EMBL; CH471052; EAW78267.1; -; Genomic_DNA. DR EMBL; AF002816; AAC78443.1; -; mRNA. DR EMBL; AF004836; AAC78444.1; ALT_INIT; Genomic_DNA. DR EMBL; AF104913; AAC82471.1; ALT_INIT; mRNA. DR EMBL; AJ001046; CAA04500.1; -; mRNA. DR CCDS; CCDS3259.1; -. [Q04637-1] DR CCDS; CCDS3260.1; -. [Q04637-4] DR CCDS; CCDS3261.1; -. [Q04637-5] DR CCDS; CCDS46970.2; -. [Q04637-7] DR CCDS; CCDS54687.1; -. [Q04637-9] DR CCDS; CCDS54688.1; -. [Q04637-8] DR CCDS; CCDS77866.1; -. [Q04637-3] DR PIR; A44453; A44453. DR RefSeq; NP_001181875.2; NM_001194946.2. [Q04637-9] DR RefSeq; NP_001181876.2; NM_001194947.2. [Q04637-9] DR RefSeq; NP_001278086.2; NM_001291157.2. [Q04637-3] DR RefSeq; NP_004944.3; NM_004953.4. [Q04637-7] DR RefSeq; NP_886553.3; NM_182917.4. DR RefSeq; NP_937884.2; NM_198241.3. [Q04637-1] DR RefSeq; NP_937885.1; NM_198242.3. [Q04637-5] DR RefSeq; NP_937887.2; NM_198244.3. [Q04637-4] DR PDB; 1LJ2; X-ray; 2.38 A; C/D=172-199. DR PDB; 1UG3; X-ray; 2.24 A; A/B=1233-1571. DR PDB; 2W97; X-ray; 2.29 A; E/F=609-622. DR PDB; 4AZA; X-ray; 2.16 A; B/D=609-620. DR PDB; 4F02; X-ray; 2.00 A; C/F=178-203. DR PDB; 5EHC; X-ray; 2.40 A; B=609-622. DR PDB; 5EI3; X-ray; 1.71 A; B=609-622. DR PDB; 5EIR; X-ray; 2.69 A; B=609-622. DR PDB; 5T46; X-ray; 1.53 A; B/D=592-653. DR PDB; 5ZK5; X-ray; 2.25 A; B=609-623. DR PDB; 6ZMW; EM; 3.70 A; g=290-1599. DR PDB; 8HUJ; EM; 3.76 A; B=746-992. DR PDB; 8J7R; EM; 3.70 A; B=746-992. DR PDB; 8OZ0; EM; 3.50 A; 2=197-1599. DR PDBsum; 1LJ2; -. DR PDBsum; 1UG3; -. DR PDBsum; 2W97; -. DR PDBsum; 4AZA; -. DR PDBsum; 4F02; -. DR PDBsum; 5EHC; -. DR PDBsum; 5EI3; -. DR PDBsum; 5EIR; -. DR PDBsum; 5T46; -. DR PDBsum; 5ZK5; -. DR PDBsum; 6ZMW; -. DR PDBsum; 8HUJ; -. DR PDBsum; 8J7R; -. DR PDBsum; 8OZ0; -. DR AlphaFoldDB; Q04637; -. DR BMRB; Q04637; -. DR EMDB; EMD-11302; -. DR EMDB; EMD-17297; -. DR EMDB; EMD-35041; -. DR EMDB; EMD-36046; -. DR SMR; Q04637; -. DR BioGRID; 108296; 468. DR ComplexPortal; CPX-2666; Eukaryotic translation initiation factor 4F, EIF4A1 and EIF4G1 variant. DR ComplexPortal; CPX-5634; Eukaryotic translation initiation factor 4F, EIF4A2 and EIF4G1 variant. DR CORUM; Q04637; -. DR DIP; DIP-1161N; -. DR ELM; Q04637; -. DR FunCoup; Q04637; 2647. DR IntAct; Q04637; 183. DR MINT; Q04637; -. DR STRING; 9606.ENSP00000416255; -. DR BindingDB; Q04637; -. DR ChEMBL; CHEMBL4523621; -. DR MoonProt; Q04637; -. DR GlyConnect; 2847; 1 O-GlcNAc glycan (1 site). DR GlyCosmos; Q04637; 6 sites, 1 glycan. DR GlyGen; Q04637; 24 sites, 1 N-linked glycan (1 site), 1 O-linked glycan (19 sites). DR iPTMnet; Q04637; -. DR MetOSite; Q04637; -. DR PhosphoSitePlus; Q04637; -. DR SwissPalm; Q04637; -. DR BioMuta; EIF4G1; -. DR DMDM; 294862538; -. DR jPOST; Q04637; -. DR MassIVE; Q04637; -. DR PaxDb; 9606-ENSP00000416255; -. DR PeptideAtlas; Q04637; -. DR ProteomicsDB; 20132; -. DR ProteomicsDB; 34026; -. DR ProteomicsDB; 58250; -. [Q04637-1] DR ProteomicsDB; 58251; -. [Q04637-3] DR ProteomicsDB; 58252; -. [Q04637-4] DR ProteomicsDB; 58253; -. [Q04637-5] DR ProteomicsDB; 58254; -. [Q04637-6] DR Pumba; Q04637; -. DR Antibodypedia; 3406; 617 antibodies from 40 providers. DR DNASU; 1981; -. DR Ensembl; ENST00000342981.8; ENSP00000343450.4; ENSG00000114867.23. [Q04637-8] DR Ensembl; ENST00000346169.7; ENSP00000316879.5; ENSG00000114867.23. [Q04637-1] DR Ensembl; ENST00000350481.9; ENSP00000317600.8; ENSG00000114867.23. [Q04637-5] DR Ensembl; ENST00000352767.7; ENSP00000338020.4; ENSG00000114867.23. [Q04637-9] DR Ensembl; ENST00000382330.7; ENSP00000371767.3; ENSG00000114867.23. [Q04637-9] DR Ensembl; ENST00000392537.6; ENSP00000376320.2; ENSG00000114867.23. [Q04637-4] DR Ensembl; ENST00000414031.5; ENSP00000391935.1; ENSG00000114867.23. [Q04637-3] DR Ensembl; ENST00000424196.5; ENSP00000416255.1; ENSG00000114867.23. [Q04637-9] DR Ensembl; ENST00000434061.6; ENSP00000411826.2; ENSG00000114867.23. [Q04637-7] DR GeneID; 1981; -. DR KEGG; hsa:1981; -. DR MANE-Select; ENST00000346169.7; ENSP00000316879.5; NM_198241.3; NP_937884.2. DR UCSC; uc003fnp.4; human. [Q04637-1] DR AGR; HGNC:3296; -. DR ClinPGx; PA27722; -. DR CTD; 1981; -. DR DisGeNET; 1981; -. DR GeneCards; EIF4G1; -. DR HGNC; HGNC:3296; EIF4G1. DR HPA; ENSG00000114867; Tissue enhanced (skeletal). DR MalaCards; EIF4G1; -. DR MIM; 600495; gene. DR MIM; 614251; phenotype. DR OpenTargets; ENSG00000114867; -. DR Orphanet; 411602; Hereditary late-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000114867; -. DR eggNOG; KOG0401; Eukaryota. DR GeneTree; ENSGT00940000154648; -. DR HOGENOM; CLU_001519_2_0_1; -. DR InParanoid; Q04637; -. DR OMA; PRGGPNM; -. DR OrthoDB; 514777at2759; -. DR PAN-GO; Q04637; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q04637; -. DR PathwayCommons; Q04637; -. DR Reactome; R-HSA-1169408; ISG15 antiviral mechanism. DR Reactome; R-HSA-156827; L13a-mediated translational silencing of Ceruloplasmin expression. DR Reactome; R-HSA-166208; mTORC1-mediated signalling. DR Reactome; R-HSA-429947; Deadenylation of mRNA. DR Reactome; R-HSA-450408; AUF1 (hnRNP D0) binds and destabilizes mRNA. DR Reactome; R-HSA-72649; Translation initiation complex formation. DR Reactome; R-HSA-72662; Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S. DR Reactome; R-HSA-72702; Ribosomal scanning and start codon recognition. DR Reactome; R-HSA-72706; GTP hydrolysis and joining of the 60S ribosomal subunit. DR Reactome; R-HSA-9010553; Regulation of expression of SLITs and ROBOs. DR Reactome; R-HSA-975956; Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC). DR Reactome; R-HSA-975957; Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC). DR Reactome; R-HSA-9820841; M-decay: degradation of maternal mRNAs by maternally stored factors. DR Reactome; R-HSA-9820865; Z-decay: degradation of maternal mRNAs by zygotically expressed factors. DR SignaLink; Q04637; -. DR SIGNOR; Q04637; -. DR Agora; ENSG00000114867; -. DR BioGRID-ORCS; 1981; 612 hits in 1167 CRISPR screens. DR CD-CODE; 232F8A39; P-body. DR CD-CODE; DEE660B4; Stress granule. DR CD-CODE; E1879998; Synthetic Condensate 000375. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; EIF4G1; human. DR EvolutionaryTrace; Q04637; -. DR GeneWiki; Eukaryotic_translation_initiation_factor_4_gamma; -. DR GenomeRNAi; 1981; -. DR Pharos; Q04637; Tbio. DR PRO; PR:Q04637; -. DR Proteomes; UP000005640; Chromosome 3. DR RNAct; Q04637; protein. DR Bgee; ENSG00000114867; Expressed in gastrocnemius and 206 other cell types or tissues. DR ExpressionAtlas; Q04637; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:AgBase. DR GO; GO:0010494; C:cytoplasmic stress granule; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0016281; C:eukaryotic translation initiation factor 4F complex; IDA:ParkinsonsUK-UCL. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005840; C:ribosome; IMP:ParkinsonsUK-UCL. DR GO; GO:0005524; F:ATP binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0008190; F:eukaryotic initiation factor 4E binding; IDA:AgBase. DR GO; GO:0060090; F:molecular adaptor activity; TAS:ParkinsonsUK-UCL. DR GO; GO:0003729; F:mRNA binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0008135; F:translation factor activity, RNA binding; IMP:ParkinsonsUK-UCL. DR GO; GO:0003743; F:translation initiation factor activity; IDA:UniProtKB. DR GO; GO:0031369; F:translation initiation factor binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0001662; P:behavioral fear response; IEA:Ensembl. DR GO; GO:0002191; P:cap-dependent translational initiation; TAS:ParkinsonsUK-UCL. DR GO; GO:0031669; P:cellular response to nutrient levels; IMP:ParkinsonsUK-UCL. DR GO; GO:0097009; P:energy homeostasis; IMP:ParkinsonsUK-UCL. DR GO; GO:0035278; P:miRNA-mediated gene silencing by inhibition of translation; IDA:ParkinsonsUK-UCL. DR GO; GO:0010507; P:negative regulation of autophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:0030182; P:neuron differentiation; IEA:Ensembl. DR GO; GO:0030307; P:positive regulation of cell growth; IMP:ParkinsonsUK-UCL. DR GO; GO:1905537; P:positive regulation of eukaryotic translation initiation factor 4F complex assembly; IMP:ParkinsonsUK-UCL. DR GO; GO:1900087; P:positive regulation of G1/S transition of mitotic cell cycle; IMP:ParkinsonsUK-UCL. DR GO; GO:0045666; P:positive regulation of neuron differentiation; IEA:Ensembl. DR GO; GO:1904377; P:positive regulation of protein localization to cell periphery; IGI:ParkinsonsUK-UCL. DR GO; GO:0051247; P:positive regulation of protein metabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:0036493; P:positive regulation of translation in response to endoplasmic reticulum stress; IMP:UniProtKB. DR GO; GO:0080135; P:regulation of cellular response to stress; TAS:ParkinsonsUK-UCL. DR GO; GO:1905606; P:regulation of presynapse assembly; IGI:ARUK-UCL. DR GO; GO:0006446; P:regulation of translational initiation; IMP:UniProtKB. DR GO; GO:0006412; P:translation; IMP:ParkinsonsUK-UCL. DR GO; GO:0006413; P:translational initiation; IDA:UniProtKB. DR CDD; cd11559; W2_eIF4G1_like; 1. DR DisProt; DP02398; -. DR DisProt; DP03499; -. [Q04637-8] DR FunFam; 1.25.40.180:FF:000001; Eukaryotic translation initiation factor 4 gamma, 3, putative; 1. DR FunFam; 1.25.40.180:FF:000002; Eukaryotic translation initiation factor 4 gamma, 3, putative; 1. DR FunFam; 1.25.40.180:FF:000003; Putative eukaryotic translation initiation factor 4 gamma 1; 1. DR Gene3D; 1.25.40.180; -; 3. DR InterPro; IPR016024; ARM-type_fold. DR InterPro; IPR003891; Initiation_fac_eIF4g_MI. DR InterPro; IPR003890; MIF4G-like_typ-3. DR InterPro; IPR003307; W2_domain. DR PANTHER; PTHR23253; EUKARYOTIC TRANSLATION INITIATION FACTOR 4 GAMMA; 1. DR PANTHER; PTHR23253:SF10; EUKARYOTIC TRANSLATION INITIATION FACTOR 4 GAMMA 1; 1. DR Pfam; PF02847; MA3; 1. DR Pfam; PF02854; MIF4G; 1. DR Pfam; PF02020; W2; 1. DR SMART; SM00515; eIF5C; 1. DR SMART; SM00544; MA3; 1. DR SMART; SM00543; MIF4G; 1. DR SUPFAM; SSF48371; ARM repeat; 3. DR PROSITE; PS51366; MI; 1. DR PROSITE; PS51363; W2; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative initiation; Alternative splicing; KW Cytoplasm; Disease variant; Host-virus interaction; Initiation factor; KW Methylation; Neurodegeneration; Nucleus; Parkinson disease; Parkinsonism; KW Phosphoprotein; Protein biosynthesis; Proteomics identification; KW Reference proteome; RNA-binding; Translation regulation; KW Translational shunt. FT CHAIN 1..1599 FT /note="Eukaryotic translation initiation factor 4 gamma 1" FT /id="PRO_0000007786" FT DOMAIN 565..792 FT /note="MIF4G" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00698" FT DOMAIN 1241..1363 FT /note="MI" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00698" FT DOMAIN 1433..1599 FT /note="W2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00695" FT REGION 1..77 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 166..222 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 172..200 FT /note="PABPC1-binding" FT REGION 239..319 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 332..600 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 607..618 FT /note="EIF4E-binding" FT REGION 667..713 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 682..1085 FT /note="eIF3/EIF4A-binding" FT REGION 731..757 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1024..1227 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1450..1599 FT /note="EIF4A-binding" FT REGION 1585..1599 FT /note="Necessary but not sufficient for MKNK1-binding" FT COMPBIAS 8..24 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 34..48 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 53..72 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 249..260 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 261..271 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 289..304 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 429..452 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 453..474 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 519..535 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 548..563 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 574..583 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 674..683 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 693..703 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 741..757 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1116..1134 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1146..1178 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1186..1225 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 674..675 FT /note="Cleavage; by foot-and-mouth disease virus leader FT protease" FT SITE 681..682 FT /note="Cleavage; by enterovirus/rhinovirus protease 2A" FT MOD_RES 15 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q6NZJ6" FT MOD_RES 73 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES 110 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES 207 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 223 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 314 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 602 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q6NZJ6" FT MOD_RES 647 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 685 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES 694 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES 1028 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 1032 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES 1042 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES 1077 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1092 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17924679, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 1095 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 1145 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1147 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1185 FT /note="Phosphoserine; by PKC/PRKCA" FT /evidence="ECO:0000269|PubMed:21576361, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1187 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 1194 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1209 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1211 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692" FT MOD_RES 1231 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:16964243, FT ECO:0007744|PubMed:17081983, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 1238 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1596 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT VAR_SEQ 1..196 FT /note="Missing (in isoform E and isoform 7)" FT /evidence="ECO:0000303|PubMed:1429670" FT /id="VSP_018723" FT VAR_SEQ 1..164 FT /note="Missing (in isoform D)" FT /evidence="ECO:0000305" FT /id="VSP_018722" FT VAR_SEQ 1..87 FT /note="Missing (in isoform C)" FT /evidence="ECO:0000303|PubMed:9418880" FT /id="VSP_018721" FT VAR_SEQ 1..40 FT /note="Missing (in isoform B)" FT /evidence="ECO:0000303|PubMed:9857202" FT /id="VSP_018720" FT VAR_SEQ 48 FT /note="R -> RQGGFRSL (in isoform 9)" FT /evidence="ECO:0000305" FT /id="VSP_047396" FT VAR_SEQ 696 FT /note="P -> PQ (in isoform 7 and isoform 8)" FT /evidence="ECO:0000303|PubMed:12052860, FT ECO:0000303|PubMed:1429670, ECO:0000303|PubMed:9372926, FT ECO:0000303|Ref.12" FT /id="VSP_047397" FT VARIANT 71 FT /note="P -> S (in dbSNP:rs113810947)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_066571" FT VARIANT 161 FT /note="T -> A (in dbSNP:rs13319149)" FT /evidence="ECO:0000269|PubMed:12052860, FT ECO:0000269|PubMed:17974005, ECO:0000269|PubMed:21907011, FT ECO:0000269|PubMed:9372926, ECO:0000269|PubMed:9755181" FT /id="VAR_061147" FT VARIANT 201 FT /note="R -> H (found in a patient with Rett syndrome-like FT phenotype; uncertain significance; dbSNP:rs34838305)" FT /evidence="ECO:0000269|PubMed:26740508" FT /id="VAR_079031" FT VARIANT 311 FT /note="Y -> C (in dbSNP:rs16858632)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_055704" FT VARIANT 432 FT /note="M -> V (in dbSNP:rs2178403)" FT /evidence="ECO:0000269|PubMed:12052860, FT ECO:0000269|PubMed:1429670, ECO:0000269|PubMed:21907011, FT ECO:0000269|PubMed:9372926, ECO:0007744|PubMed:19413330" FT /id="VAR_063040" FT VARIANT 466..468 FT /note="Missing" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_066572" FT VARIANT 502 FT /note="A -> V (in PARK18; dbSNP:rs111290936)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_066573" FT VARIANT 686 FT /note="G -> C (found in patients with Parkinson disease; FT uncertain significance; dbSNP:rs112019125)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_066574" FT VARIANT 696 FT /note="P -> L (in a colorectal cancer sample; somatic FT mutation; dbSNP:rs754755344)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036117" FT VARIANT 806 FT /note="I -> V (in dbSNP:rs62287499)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_066575" FT VARIANT 829 FT /note="T -> S (in dbSNP:rs111500185)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_066576" FT VARIANT 1164 FT /note="S -> R (found in a patient with Parkinson disease; FT uncertain significance; dbSNP:rs113169049)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_066577" FT VARIANT 1197 FT /note="R -> W (found in a patient with Parkinson disease; FT uncertain significance; dbSNP:rs113388242)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_066578" FT VARIANT 1205 FT /note="R -> H (in PARK18; dbSNP:rs112176450)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_066579" FT VARIANT 1229 FT /note="P -> A (in dbSNP:rs35629949)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_061148" FT VARIANT 1233 FT /note="L -> P (in dbSNP:rs2230570)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_055705" FT VARIANT 1257 FT /note="N -> S (in dbSNP:rs73053766)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_066580" FT MUTAGEN 174..178 FT /note="KRERK->AAAAA: Loss of PABPC1 binding; when FT associated with 184-AAAA-187." FT /evidence="ECO:0000269|PubMed:10996799" FT MUTAGEN 180 FT /note="I->A: Loss of PABPC1 binding." FT /evidence="ECO:0000269|PubMed:12086624" FT MUTAGEN 182 FT /note="I->A: Loss of PABPC1 binding." FT /evidence="ECO:0000269|PubMed:12086624" FT MUTAGEN 184..187 FT /note="DPNQ->AAAA: Loss of PABPC1 binding; when associated FT with 174-AAAAA-178." FT MUTAGEN 192 FT /note="I->A: Loss of PABPC1 binding." FT /evidence="ECO:0000269|PubMed:12086624" FT MUTAGEN 196 FT /note="I->A: Loss of PABPC1 binding." FT /evidence="ECO:0000269|PubMed:12086624" FT MUTAGEN 612 FT /note="Y->A,F: Abolishes binding to EIF4E." FT /evidence="ECO:0000269|PubMed:7651417" FT MUTAGEN 617..618 FT /note="LL->AA: Abolishes binding to EIF4E." FT /evidence="ECO:0000269|PubMed:7651417" FT MUTAGEN 682 FT /note="G->A,V,W,R,E: Reduced cleavage by protease 2A from FT human rhinovirus 2." FT /evidence="ECO:0000269|PubMed:8961935" FT MUTAGEN 768 FT /note="L->A: Abolishes binding to EIF4A; when associated FT with A-770 and A-775." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 771 FT /note="L->A: Abolishes binding to EIF4A; when associated FT with A-767 and A-775." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 776 FT /note="F->A: Abolishes binding to EIF4A; when associated FT with A-767 and A-770." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 842..843 FT /note="LL->AA: Abolishes binding to EIF4A; when associated FT with A-850 and K-851." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 851..852 FT /note="FE->AK: Abolishes binding to EIF4A; when associated FT with A-841 and A-842." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 896 FT /note="L->A: Abolishes binding to EIF4A; when associated FT with A-92 and A-95." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 902 FT /note="I->A: Abolishes binding to EIF4A; when associated FT with A-895 and A-95." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 905 FT /note="L->A: Abolishes binding to EIF4A; when associated FT with A-895 and A-92." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 974 FT /note="R->A: Abolishes binding to EIF4A; when associated FT with A-976." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 977 FT /note="F->A: Abolishes binding to EIF4A; when associated FT with A-973." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 985 FT /note="L->A: Slightly reduced binding to EIF4A; when FT associated with A-989." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 990 FT /note="W->A: Slightly reduced binding to EIF4A; when FT associated with A-984." FT /evidence="ECO:0000269|PubMed:9372926" FT CONFLICT 30 FT /note="P -> R (in Ref. 9; AAC78443)" FT /evidence="ECO:0000305" FT CONFLICT 138 FT /note="F -> L (in Ref. 5; AAL92872/AAM69365)" FT /evidence="ECO:0000305" FT CONFLICT 149 FT /note="Q -> R (in Ref. 5; AAL92872/AAM69365)" FT /evidence="ECO:0000305" FT CONFLICT 214 FT /note="G -> S (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 462 FT /note="E -> D (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 468 FT /note="A -> V (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 474 FT /note="A -> G (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 479 FT /note="G -> R (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 604 FT /note="L -> P (in Ref. 1; BAA02185, 5; AAL92872/AAM69365 FT and 10; AAC82471)" FT /evidence="ECO:0000305" FT CONFLICT 625..626 FT /note="AS -> CQ (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 693 FT /note="P -> A (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 696 FT /note="P -> A (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 764 FT /note="V -> W (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 878 FT /note="G -> E (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 894 FT /note="R -> C (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 1104 FT /note="K -> Q (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 1121 FT /note="N -> I (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 1185 FT /note="S -> T (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 1384 FT /note="C -> Y (in Ref. 6; CAI46013)" FT /evidence="ECO:0000305" FT CONFLICT 1472 FT /note="Missing (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT STRAND 181..183 FT /evidence="ECO:0007829|PDB:1LJ2" FT HELIX 185..187 FT /evidence="ECO:0007829|PDB:4F02" FT HELIX 193..197 FT /evidence="ECO:0007829|PDB:4F02" FT HELIX 614..618 FT /evidence="ECO:0007829|PDB:5T46" FT TURN 619..622 FT /evidence="ECO:0007829|PDB:5T46" FT HELIX 624..627 FT /evidence="ECO:0007829|PDB:5T46" FT TURN 637..639 FT /evidence="ECO:0007829|PDB:5T46" FT HELIX 1234..1256 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1259..1267 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1272..1274 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1275..1286 FT /evidence="ECO:0007829|PDB:1UG3" FT TURN 1287..1289 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1291..1306 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1312..1329 FT /evidence="ECO:0007829|PDB:1UG3" FT TURN 1330..1332 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1336..1344 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1345..1348 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1355..1362 FT /evidence="ECO:0007829|PDB:1UG3" FT TURN 1363..1365 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1366..1369 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1372..1387 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1389..1398 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1403..1405 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1413..1419 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1423..1425 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1439..1452 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1457..1467 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1470..1473 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1476..1489 FT /evidence="ECO:0007829|PDB:1UG3" FT STRAND 1494..1496 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1501..1514 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1518..1534 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1541..1551 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1557..1563 FT /evidence="ECO:0007829|PDB:1UG3" FT INIT_MET Q04637-4:1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:22814378" FT MOD_RES Q04637-4:2 FT /note="N-acetylmethionine" FT /evidence="ECO:0007744|PubMed:22814378" FT MOD_RES Q04637-7:489 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES Q04637-7:498 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES Q04637-7:509 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES Q04637-8:685 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES Q04637-8:694 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES Q04637-8:705 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" SQ SEQUENCE 1599 AA; 175491 MW; 324088B60863DA34 CRC64; MNKAPQSTGP PPAPSPGLPQ PAFPPGQTAP VVFSTPQATQ MNTPSQPRQH FYPSRAQPPS SAASRVQSAA PARPGPAAHV YPAGSQVMMI PSQISYPASQ GAYYIPGQGR STYVVPTQQY PVQPGAPGFY PGASPTEFGT YAGAYYPAQG VQQFPTGVAP TPVLMNQPPQ IAPKRERKTI RIRDPNQGGK DITEEIMSGA RTASTPTPPQ TGGGLEPQAN GETPQVAVIV RPDDRSQGAI IADRPGLPGP EHSPSESQPS SPSPTPSPSP VLEPGSEPNL AVLSIPGDTM TTIQMSVEES TPISRETGEP YRLSPEPTPL AEPILEVEVT LSKPVPESEF SSSPLQAPTP LASHTVEIHE PNGMVPSEDL EPEVESSPEL APPPACPSES PVPIAPTAQP EELLNGAPSP PAVDLSPVSE PEEQAKEVTA SMAPPTIPSA TPATAPSATS PAQEEEMEEE EEEEEGEAGE AGEAESEKGG EELLPPESTP IPANLSQNLE AAAATQVAVS VPKRRRKIKE LNKKEAVGDL LDAFKEANPA VPEVENQPPA GSNPGPESEG SGVPPRPEEA DETWDSKEDK IHNAENIQPG EQKYEYKSDQ WKPLNLEEKK RYDREFLLGF QFIFASMQKP EGLPHISDVV LDKANKTPLR PLDPTRLQGI NCGPDFTPSF ANLGRTTLST RGPPRGGPGG ELPRGPAGLG PRRSQQGPRK EPRKIIATVL MTEDIKLNKA EKAWKPSSKR TAADKDRGEE DADGSKTQDL FRRVRSILNK LTPQMFQQLM KQVTQLAIDT EERLKGVIDL IFEKAISEPN FSVAYANMCR CLMALKVPTT EKPTVTVNFR KLLLNRCQKE FEKDKDDDEV FEKKQKEMDE AATAEERGRL KEELEEARDI ARRRSLGNIK FIGELFKLKM LTEAIMHDCV VKLLKNHDEE SLECLCRLLT TIGKDLDFEK AKPRMDQYFN QMEKIIKEKK TSSRIRFMLQ DVLDLRGSNW VPRRGDQGPK TIDQIHKEAE MEEHREHIKV QQLMAKGSDK RRGGPPGPPI SRGLPLVDDG GWNTVPISKG SRPIDTSRLT KITKPGSIDS NNQLFAPGGR LSWGKGSSGG SGAKPSDAAS EAARPATSTL NRFSALQQAV PTESTDNRRV VQRSSLSRER GEKAGDRGDR LERSERGGDR GDRLDRARTP ATKRSFSKEV EERSRERPSQ PEGLRKAASL TEDRDRGRDA VKREAALPPV SPLKAALSEE ELEKKSKAII EEYLHLNDMK EAVQCVQELA SPSLLFIFVR HGVESTLERS AIAREHMGQL LHQLLCAGHL STAQYYQGLY EILELAEDME IDIPHVWLYL AELVTPILQE GGVPMGELFR EITKPLRPLG KAASLLLEIL GLLCKSMGPK KVGTLWREAG LSWKEFLPEG QDIGAFVAEQ KVEYTLGEES EAPGQRALPS EELNRQLEKL LKEGSSNQRV FDWIEANLSE QQIVSNTLVR ALMTAVCYSA IIFETPLRVD VAVLKARAKL LQKYLCDEQK ELQALYALQA LVVTLEQPPN LLRMFFDALY DEDVVKEDAF YSWESSKDPA EQQGKGVALK SVTAFFKWLR EAEEESDHN // ID PRKN_HUMAN Reviewed; 465 AA. AC O60260; A3FG77; A8K975; D3JZW7; D3K2X0; Q5TFV8; Q5VVX4; Q6Q2I6; Q8NI41; AC Q8NI43; Q8NI44; Q8WW07; DT 11-OCT-2004, integrated into UniProtKB/Swiss-Prot. DT 17-OCT-2006, sequence version 2. DT 28-JAN-2026, entry version 236. DE RecName: Full=E3 ubiquitin-protein ligase parkin {ECO:0000305}; DE Short=Parkin; DE EC=2.3.2.31 {ECO:0000269|PubMed:23770887, ECO:0000269|PubMed:32047033}; DE AltName: Full=Parkin RBR E3 ubiquitin-protein ligase {ECO:0000312|HGNC:HGNC:8607}; DE AltName: Full=Parkinson juvenile disease protein 2; DE Short=Parkinson disease protein 2; GN Name=PRKN {ECO:0000312|HGNC:HGNC:8607}; Synonyms=PARK2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), INVOLVEMENT IN PARK2, AND RP TISSUE SPECIFICITY. RC TISSUE=Fetal brain, and Skeletal muscle; RX PubMed=9560156; DOI=10.1038/33416; RA Kitada T., Asakawa S., Hattori N., Matsumine H., Yamamura Y., Minoshima S., RA Yokochi M., Mizuno Y., Shimizu N.; RT "Mutations in the parkin gene cause autosomal recessive juvenile RT parkinsonism."; RL Nature 392:605-608(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, TISSUE SPECIFICITY, RP VARIANTS ARG-311 AND THR-371, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=19501131; DOI=10.1016/j.neulet.2009.05.079; RA Kasap M., Akpinar G., Sazci A., Idrisoglu H.A., Vahaboglu H.; RT "Evidence for the presence of full-length PARK2 mRNA and Parkin protein in RT human blood."; RL Neurosci. Lett. 460:196-200(2009). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3 AND 4). RA D'Agata V., Scapagnini G., Cavallaro S.; RT "Functional and molecular diversity of parkin."; RL Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 7 AND 8). RC TISSUE=Retina; RA Campello L., Esteve-Rudd J., Cuenca N., Martin-Nieto J.; RT "Homo sapiens PARK2 transcript variants."; RL Submitted (DEC-2009) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). 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=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 [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 5). RC TISSUE=Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 312-361. RA Zou H.Q., Chan P.; RL Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases. RN [10] RP SUBCELLULAR LOCATION. RX PubMed=10319893; RX DOI=10.1002/1531-8249(199905)45:5<668::aid-ana19>3.0.co;2-z; RA Shimura H., Hattori N., Kubo S., Yoshikawa M., Kitada T., Matsumine H., RA Asakawa S., Minoshima S., Yamamura Y., Shimizu N., Mizuno Y.; RT "Immunohistochemical and subcellular localization of Parkin protein: RT absence of protein in autosomal recessive juvenile parkinsonism patients."; RL Ann. Neurol. 45:668-672(1999). RN [11] RP FUNCTION IN UBIQUITINATION. RX PubMed=10973942; DOI=10.1074/jbc.c000447200; RA Imai Y., Soda M., Takahashi R.; RT "Parkin suppresses unfolded protein stress-induced cell death through its RT E3 ubiquitin-protein ligase activity."; RL J. Biol. Chem. 275:35661-35664(2000). RN [12] RP FUNCTION, AND CHARACTERIZATION OF VARIANTS PARK2 PRO-42 AND ARG-240. RX PubMed=10888878; DOI=10.1038/77060; RA Shimura H., Hattori N., Kubo S., Mizuno Y., Asakawa S., Minoshima S., RA Shimizu N., Iwai K., Chiba T., Tanaka K., Suzuki T.; RT "Familial Parkinson disease gene product, parkin, is a ubiquitin-protein RT ligase."; RL Nat. Genet. 25:302-305(2000). RN [13] RP INTERACTION WITH UBE2L6 AND SEPTIN5, AND UBIQUITINATION OF SEPTIN5. RX PubMed=11078524; DOI=10.1073/pnas.240347797; RA Zhang Y., Gao J., Chung K.K.K., Huang H., Dawson V.L., Dawson T.M.; RT "Parkin functions as an E2-dependent ubiquitin-protein ligase and promotes RT the degradation of the synaptic vesicle-associated protein, CDCrel-1."; RL Proc. Natl. Acad. Sci. U.S.A. 97:13354-13359(2000). RN [14] RP UBIQUITINATION OF GPR37. RX PubMed=11439185; DOI=10.1016/s0092-8674(01)00407-x; RA Imai Y., Soda M., Inoue H., Hattori N., Mizuno Y., Takahashi R.; RT "An unfolded putative transmembrane polypeptide, which can lead to RT endoplasmic reticulum stress, is a substrate of Parkin."; RL Cell 105:891-902(2001). RN [15] RP FUNCTION, INTERACTION WITH SNCAIP, CHARACTERIZATION OF VARIANTS PARK2 RP ARG-240; CYS-256; TRP-275 AND ASN-415, AND MUTAGENESIS OF CYS-337; CYS-421 RP AND CYS-431. RX PubMed=11590439; DOI=10.1038/nm1001-1144; RA Chung K.K.K., Zhang Y., Lim K.L., Tanaka Y., Huang H., Gao J., Ross C.A., RA Dawson V.L., Dawson T.M.; RT "Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: RT implications for Lewy-body formation in Parkinson disease."; RL Nat. Med. 7:1144-1150(2001). RN [16] RP FUNCTION, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS PARK2 RP PRO-42 AND ARG-240. RX PubMed=11431533; DOI=10.1126/science.1060627; RA Shimura H., Schlossmacher M.G., Hattori N., Frosch M.P., Trockenbacher A., RA Schneider R., Mizuno Y., Kosik K.S., Selkoe D.J.; RT "Ubiquitination of a new form of alpha-synuclein by parkin from human RT brain: implications for Parkinson's disease."; RL Science 293:263-269(2001). RN [17] RP PRESENCE OF ATYPICAL RING FINGER DOMAINS. RX PubMed=12446796; DOI=10.1093/oxfordjournals.molbev.a004029; RA Marin I., Ferrus A.; RT "Comparative genomics of the RBR family, including the Parkinson's disease- RT related gene parkin and the genes of the ariadne subfamily."; RL Mol. Biol. Evol. 19:2039-2050(2002). RN [18] RP FUNCTION, INTERACTION WITH STUB1; HSP70 AND GPR37, AND UBIQUITINATION OF RP STUB1. RX PubMed=12150907; DOI=10.1016/s1097-2765(02)00583-x; RA Imai Y., Soda M., Hatakeyama S., Akagi T., Hashikawa T., Nakayama K., RA Takahashi R.; RT "CHIP is associated with Parkin, a gene responsible for familial RT Parkinson's disease, and enhances its ubiquitin ligase activity."; RL Mol. Cell 10:55-67(2002). RN [19] RP INTERACTION WITH SYT11, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF RP VARIANTS PARK2 GLY-289 AND ARG-418. RX PubMed=12925569; DOI=10.1093/hmg/ddg269; RA Huynh D.P., Scoles D.R., Nguyen D., Pulst S.M.; RT "The autosomal recessive juvenile Parkinson disease gene product, parkin, RT interacts with and ubiquitinates synaptotagmin XI."; RL Hum. Mol. Genet. 12:2587-2597(2003). RN [20] RP INTERACTION WITH PACRG. RX PubMed=14532270; DOI=10.1074/jbc.m309655200; RA Imai Y., Soda M., Murakami T., Shoji M., Abe K., Takahashi R.; RT "A product of the human gene adjacent to parkin is a component of Lewy RT bodies and suppresses Pael receptor-induced cell death."; RL J. Biol. Chem. 278:51901-51910(2003). RN [21] RP FUNCTION, INTERACTION WITH FBXW7 AND CUL1, TISSUE SPECIFICITY, AND RP UBIQUITINATION OF CYCLIN E. RX PubMed=12628165; DOI=10.1016/s0896-6273(03)00084-9; RA Staropoli J.F., McDermott C., Martinat C., Schulman B., Demireva E., RA Abeliovich A.; RT "Parkin is a component of an SCF-like ubiquitin ligase complex and protects RT postmitotic neurons from kainate excitotoxicity."; RL Neuron 37:735-749(2003). RN [22] RP INVOLVEMENT IN CANCER, AND TISSUE SPECIFICITY. RX PubMed=14614460; DOI=10.1038/sj.onc.1207072; RA Denison S.R., Wang F., Becker N.A., Schuele B., Kock N., Phillips L.A., RA Klein C., Smith D.I.; RT "Alterations in the common fragile site gene Parkin in ovarian and other RT cancers."; RL Oncogene 22:8370-8378(2003). RN [23] RP FUNCTION, INVOLVEMENT IN CANCER, AND TISSUE SPECIFICITY. RX PubMed=12719539; DOI=10.1073/pnas.0931262100; RA Cesari R., Martin E.S., Calin G.A., Pentimalli F., Bichi R., McAdams H., RA Trapasso F., Drusco A., Shimizu M., Masciullo V., D'Andrilli G., RA Scambia G., Picchio M.C., Alder H., Godwin A.K., Croce C.M.; RT "Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is RT a candidate tumor suppressor gene on chromosome 6q25-q27."; RL Proc. Natl. Acad. Sci. U.S.A. 100:5956-5961(2003). RN [24] RP REVIEW. RX PubMed=15229644; DOI=10.1038/sj.embor.7400188; RA Kahle P.J., Haass C.; RT "How does parkin ligate ubiquitin to Parkinson's disease?"; RL EMBO Rep. 5:681-685(2004). RN [25] RP FUNCTION, UBIQUITINATION, AND S-NITROSYLATION. RX PubMed=15105460; DOI=10.1126/science.1093891; RA Chung K.K.K., Thomas B., Li X., Pletnikova O., Troncoso J.C., Marsh L., RA Dawson V.L., Dawson T.M.; RT "S-nitrosylation of parkin regulates ubiquitination and compromises RT parkin's protective function."; RL Science 304:1328-1331(2004). RN [26] RP INTERACTION WITH PSMA7. RX PubMed=15987638; DOI=10.1016/j.febslet.2005.06.003; RA Dachsel J.C., Lucking C.B., Deeg S., Schultz E., Lalowski M., RA Casademunt E., Corti O., Hampe C., Patenge N., Vaupel K., Yamamoto A., RA Dichgans M., Brice A., Wanker E.E., Kahle P.J., Gasser T.; RT "Parkin interacts with the proteasome subunit alpha4."; RL FEBS Lett. 579:3913-3919(2005). RN [27] RP FUNCTION, AND INTERACTION WITH SNCAIP. RX PubMed=15728840; DOI=10.1523/jneurosci.4474-04.2005; RA Lim K.L., Chew K.C., Tan J.M., Wang C., Chung K.K., Zhang Y., Tanaka Y., RA Smith W., Engelender S., Ross C.A., Dawson V.L., Dawson T.M.; RT "Parkin mediates nonclassical, proteasomal-independent ubiquitination of RT synphilin-1: implications for Lewy body formation."; RL J. Neurosci. 25:2002-2009(2005). RN [28] RP FUNCTION, AND INTERACTION WITH AIMP2. RX PubMed=16135753; DOI=10.1523/jneurosci.2172-05.2005; RA Ko H.S., von Coelln R., Sriram S.R., Kim S.W., Chung K.K.K., Pletnikova O., RA Troncoso J., Johnson B., Saffary R., Goh E.L., Song H., Park B.-J., RA Kim M.J., Kim S., Dawson V.L., Dawson T.M.; RT "Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase RT cofactor, p38/JTV-1, leads to catecholaminergic cell death."; RL J. Neurosci. 25:7968-7978(2005). RN [29] RP INTERACTION WITH LRRK2. RX PubMed=16352719; DOI=10.1073/pnas.0508052102; RA Smith W.W., Pei Z., Jiang H., Moore D.J., Liang Y., West A.B., Dawson V.L., RA Dawson T.M., Ross C.A.; RT "Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin and mutant RT LRRK2 induces neuronal degeneration."; RL Proc. Natl. Acad. Sci. U.S.A. 102:18676-18681(2005). RN [30] RP INTERACTION WITH RANBP2. RX PubMed=16332688; DOI=10.1074/jbc.m504994200; RA Um J.W., Min D.S., Rhim H., Kim J., Paik S.R., Chung K.C.; RT "Parkin ubiquitinates and promotes the degradation of RanBP2."; RL J. Biol. Chem. 281:3595-3603(2006). RN [31] RP INTERACTION WITH SUMO1, AND SUBCELLULAR LOCATION. RX PubMed=16955485; DOI=10.1002/jnr.21041; RA Um J.W., Chung K.C.; RT "Functional modulation of parkin through physical interaction with SUMO- RT 1."; RL J. Neurosci. Res. 84:1543-1554(2006). RN [32] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=17846173; DOI=10.1083/jcb.200611128; RA Olzmann J.A., Li L., Chudaev M.V., Chen J., Perez F.A., Palmiter R.D., RA Chin L.S.; RT "Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to RT aggresomes via binding to HDAC6."; RL J. Cell Biol. 178:1025-1038(2007). RN [33] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT THR-175 AND THR-217, AND RP MUTAGENESIS OF THR-175; THR-217 AND CYS-238. RX PubMed=18957282; DOI=10.1016/j.bbrc.2008.10.104; RA Kim Y., Park J., Kim S., Song S., Kwon S.K., Lee S.H., Kitada T., Kim J.M., RA Chung J.; RT "PINK1 controls mitochondrial localization of Parkin through direct RT phosphorylation."; RL Biochem. Biophys. Res. Commun. 377:975-980(2008). RN [34] RP FUNCTION IN MITOCHONDRIAL AUTOPHAGY, AND SUBCELLULAR LOCATION. RX PubMed=19029340; DOI=10.1083/jcb.200809125; RA Narendra D., Tanaka A., Suen D.F., Youle R.J.; RT "Parkin is recruited selectively to impaired mitochondria and promotes RT their autophagy."; RL J. Cell Biol. 183:795-803(2008). RN [35] RP INTERACTION WITH RNF41, UBIQUITINATION, MUTAGENESIS OF CYS-421, AND RP FUNCTION. RX PubMed=18541373; DOI=10.1016/j.neulet.2008.05.052; RA Yu F., Zhou J.; RT "Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced oxidative RT stress."; RL Neurosci. Lett. 440:4-8(2008). RN [36] RP FUNCTION, COMPONENT OF A COMPLEX COMPOSED OF PRKN; PARK7 AND PINK1, RP SUBCELLULAR LOCATION, UBIQUITINATION, AND CHARACTERIZATION OF VARIANT PARK2 RP PRO-42. RX PubMed=19229105; DOI=10.1172/jci37617; RA Xiong H., Wang D., Chen L., Choo Y.S., Ma H., Tang C., Xia K., Jiang W., RA Ronai Z., Zhuang X., Zhang Z.; RT "Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting RT unfolded protein degradation."; RL J. Clin. Invest. 119:650-660(2009). RN [37] RP FUNCTION IN PROTECTION OF APOPTOSIS, CHARACTERIZATION OF VARIANTS PARK2 RP ASN-161; CYS-256; TRP-275; ARG-418 AND ARG-441, AND DOMAIN. RX PubMed=19801972; DOI=10.1038/ncb1981; RA da Costa C.A., Sunyach C., Giaime E., West A., Corti O., Brice A., Safe S., RA Abou-Sleiman P.M., Wood N.W., Takahashi H., Goldberg M.S., Shen J., RA Checler F.; RT "Transcriptional repression of p53 by parkin and impairment by mutations RT associated with autosomal recessive juvenile Parkinson's disease."; RL Nat. Cell Biol. 11:1370-1375(2009). RN [38] RP INTERACTION WITH PINK1. RX PubMed=20798600; DOI=10.4161/auto.6.7.13286; RA Geisler S., Holmstrom K.M., Treis A., Skujat D., Weber S.S., Fiesel F.C., RA Kahle P.J., Springer W.; RT "The PINK1/Parkin-mediated mitophagy is compromised by PD-associated RT mutations."; RL Autophagy 6:871-878(2010). RN [39] RP FUNCTION, INTERACTION WITH BCL2, SUBCELLULAR LOCATION, AND CHARACTERIZATION RP OF VARIANTS PARK2 ASN-161; ARG-240; PHE-431 AND LEU-437. RX PubMed=20889974; DOI=10.1074/jbc.m110.101469; RA Chen D., Gao F., Li B., Wang H., Xu Y., Zhu C., Wang G.; RT "Parkin mono-ubiquitinates Bcl-2 and regulates autophagy."; RL J. Biol. Chem. 285:38214-38223(2010). RN [40] RP FUNCTION IN MITOCHONDRIAL AUTOPHAGY, SUBCELLULAR LOCATION, INTERACTION WITH RP PINK1, AND CHARACTERIZATION OF VARIANTS PARK ASN-415 AND ASP-430. RX PubMed=19966284; DOI=10.1073/pnas.0911187107; RA Vives-Bauza C., Zhou C., Huang Y., Cui M., de Vries R.L., Kim J., May J., RA Tocilescu M.A., Liu W., Ko H.S., Magrane J., Moore D.J., Dawson V.L., RA Grailhe R., Dawson T.M., Li C., Tieu K., Przedborski S.; RT "PINK1-dependent recruitment of Parkin to mitochondria in mitophagy."; RL Proc. Natl. Acad. Sci. U.S.A. 107:378-383(2010). RN [41] RP FUNCTION, INTERACTION WITH ZNF746, AND CHARACTERIZATION OF VARIANTS PARK2 RP TRP-275; ASP-430 AND PHE-431. RX PubMed=21376232; DOI=10.1016/j.cell.2011.02.010; RA Shin J.H., Ko H.S., Kang H., Lee Y., Lee Y.I., Pletinkova O., RA Troconso J.C., Dawson V.L., Dawson T.M.; RT "PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration RT in Parkinson's disease."; RL Cell 144:689-702(2011). RN [42] RP CHARACTERIZATION OF VARIANTS PARK2 PRO-42 AND GLY-289. RX PubMed=20889486; DOI=10.1093/hmg/ddq428; RA Rose J.M., Novoselov S.S., Robinson P.A., Cheetham M.E.; RT "Molecular chaperone-mediated rescue of mitophagy by a Parkin RING1 domain RT mutant."; RL Hum. Mol. Genet. 20:16-27(2011). RN [43] RP FUNCTION. RX PubMed=21753002; DOI=10.1523/jneurosci.1917-11.2011; RA Van Humbeeck C., Cornelissen T., Hofkens H., Mandemakers W., Gevaert K., RA De Strooper B., Vandenberghe W.; RT "Parkin interacts with Ambra1 to induce mitophagy."; RL J. Neurosci. 31:10249-10261(2011). RN [44] RP FUNCTION, REACTION MECHANISM, AND INTERACTION WITH UBE2L3. RX PubMed=21532592; DOI=10.1038/nature09966; RA Wenzel D.M., Lissounov A., Brzovic P.S., Klevit R.E.; RT "UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT RT hybrids."; RL Nature 474:105-108(2011). RN [45] RP FUNCTION, INTERACTION WITH CHPF, AND SUBCELLULAR LOCATION. RX PubMed=22082830; DOI=10.1093/hmg/ddr530; RA Kuroda Y., Sako W., Goto S., Sawada T., Uchida D., Izumi Y., Takahashi T., RA Kagawa N., Matsumoto M., Matsumoto M., Takahashi R., Kaji R., Mitsui T.; RT "Parkin interacts with Klokin1 for mitochondrial import and maintenance of RT membrane potential."; RL Hum. Mol. Genet. 21:991-1003(2012). RN [46] RP FUNCTION, AND CHARACTERIZATION OF VARIANTS PARK2 ASN-211 AND ASN-415. RX PubMed=22396657; DOI=10.1371/journal.pgen.1002537; RA Liu S., Sawada T., Lee S., Yu W., Silverio G., Alapatt P., Millan I., RA Shen A., Saxton W., Kanao T., Takahashi R., Hattori N., Imai Y., Lu B.; RT "Parkinson's disease-associated kinase PINK1 regulates Miro protein level RT and axonal transport of mitochondria."; RL PLoS Genet. 8:E1002537-E1002537(2012). RN [47] RP PHOSPHORYLATION AT SER-65, FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=23754282; DOI=10.1074/jbc.m113.467530; RA Iguchi M., Kujuro Y., Okatsu K., Koyano F., Kosako H., Kimura M., RA Suzuki N., Uchiyama S., Tanaka K., Matsuda N.; RT "Parkin-catalyzed ubiquitin-ester transfer is triggered by PINK1-dependent RT phosphorylation."; RL J. Biol. Chem. 288:22019-22032(2013). RN [48] RP FUNCTION. RX PubMed=23685073; DOI=10.1016/j.molcel.2013.04.012; RA Haddad D.M., Vilain S., Vos M., Esposito G., Matta S., Kalscheuer V.M., RA Craessaerts K., Leyssen M., Nascimento R.M., Vianna-Morgante A.M., RA De Strooper B., Van Esch H., Morais V.A., Verstreken P.; RT "Mutations in the intellectual disability gene Ube2a cause neuronal RT dysfunction and impair parkin-dependent mitophagy."; RL Mol. Cell 50:831-843(2013). RN [49] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH FBXO7. RX PubMed=23933751; DOI=10.1038/nn.3489; RA Burchell V.S., Nelson D.E., Sanchez-Martinez A., Delgado-Camprubi M., RA Ivatt R.M., Pogson J.H., Randle S.J., Wray S., Lewis P.A., Houlden H., RA Abramov A.Y., Hardy J., Wood N.W., Whitworth A.J., Laman H., RA Plun-Favreau H.; RT "The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to RT mediate mitophagy."; RL Nat. Neurosci. 16:1257-1265(2013). RN [50] RP INTERACTION WITH BAG4; BAG5; HSPA1L; HSPA1A AND HSPA8. RX PubMed=24270810; DOI=10.1038/nature12748; RA Hasson S.A., Kane L.A., Yamano K., Huang C.H., Sliter D.A., Buehler E., RA Wang C., Heman-Ackah S.M., Hessa T., Guha R., Martin S.E., Youle R.J.; RT "High-content genome-wide RNAi screens identify regulators of parkin RT upstream of mitophagy."; RL Nature 504:291-295(2013). RN [51] RP UBIQUITINATION, MUTAGENESIS OF GLY-429, AND CHARACTERIZATION OF VARIANTS RP PARK2 ASN-415 AND ASP-430. RX PubMed=23770917; DOI=10.1038/ncomms2983; RA Spratt D.E., Martinez-Torres R.J., Noh Y.J., Mercier P., Manczyk N., RA Barber K.R., Aguirre J.D., Burchell L., Purkiss A., Walden H., Shaw G.S.; RT "A molecular explanation for the recessive nature of parkin-linked RT Parkinson's disease."; RL Nat. Commun. 4:1983-1983(2013). RN [52] RP FUNCTION IN MITOPHAGY, INTERACTION WITH MFN2, AND SUBCELLULAR LOCATION. RX PubMed=23620051; DOI=10.1126/science.1231031; RA Chen Y., Dorn G.W. II; RT "PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged RT mitochondria."; RL Science 340:471-475(2013). RN [53] RP FUNCTION, PHOSPHORYLATION AT SER-65, UBIQUITIN-BINDING, ACTIVITY RP REGULATION, AND MUTAGENESIS OF SER-65. RX PubMed=24660806; DOI=10.1042/bj20140334; RA Kazlauskaite A., Kondapalli C., Gourlay R., Campbell D.G., Ritorto M.S., RA Hofmann K., Alessi D.R., Knebel A., Trost M., Muqit M.M.; RT "Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at RT Ser65."; RL Biochem. J. 460:127-139(2014). RN [54] RP SUBCELLULAR LOCATION. RX PubMed=24898855; DOI=10.7554/elife.01958; RA Yun J., Puri R., Yang H., Lizzio M.A., Wu C., Sheng Z.H., Guo M.; RT "MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin RT and compensates for loss of PINK1/parkin."; RL Elife 3:E01958-E01958(2014). RN [55] RP FUNCTION, PHOSPHORYLATION AT SER-65, UBIQUITIN-BINDING, ACTIVITY RP REGULATION, AND MUTAGENESIS OF SER-65 AND CYS-431. RX PubMed=25474007; DOI=10.1371/journal.pgen.1004861; RA Shiba-Fukushima K., Arano T., Matsumoto G., Inoshita T., Yoshida S., RA Ishihama Y., Ryu K.Y., Nukina N., Hattori N., Imai Y.; RT "Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin RT mitochondrial tethering."; RL PLoS Genet. 10:e1004861-e1004861(2014). RN [56] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=24751536; DOI=10.1083/jcb.201402104; RA Kane L.A., Lazarou M., Fogel A.I., Li Y., Yamano K., Sarraf S.A., RA Banerjee S., Youle R.J.; RT "PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase RT activity."; RL J. Cell Biol. 205:143-153(2014). RN [57] RP FUNCTION, PHOSPHORYLATION AT SER-65, UBIQUITIN-BINDING, ACTIVITY RP REGULATION, AND MUTAGENESIS OF SER-65 AND TRP-403. RX PubMed=24784582; DOI=10.1038/nature13392; RA Koyano F., Okatsu K., Kosako H., Tamura Y., Go E., Kimura M., Kimura Y., RA Tsuchiya H., Yoshihara H., Hirokawa T., Endo T., Fon E.A., Trempe J.F., RA Saeki Y., Tanaka K., Matsuda N.; RT "Ubiquitin is phosphorylated by PINK1 to activate parkin."; RL Nature 510:162-166(2014). RN [58] RP FUNCTION. RX PubMed=24896179; DOI=10.1038/nature13418; RA Bingol B., Tea J.S., Phu L., Reichelt M., Bakalarski C.E., Song Q., RA Foreman O., Kirkpatrick D.S., Sheng M.; RT "The mitochondrial deubiquitinase USP30 opposes parkin-mediated RT mitophagy."; RL Nature 510:370-375(2014). RN [59] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=25527291; DOI=10.15252/embj.201489847; RA Wauer T., Swatek K.N., Wagstaff J.L., Gladkova C., Pruneda J.N., RA Michel M.A., Gersch M., Johnson C.M., Freund S.M., Komander D.; RT "Ubiquitin Ser65 phosphorylation affects ubiquitin structure, chain RT assembly and hydrolysis."; RL EMBO J. 34:307-325(2015). RN [60] RP FUNCTION. RX PubMed=25621951; DOI=10.1038/ncb3097; RA Cunningham C.N., Baughman J.M., Phu L., Tea J.S., Yu C., Coons M., RA Kirkpatrick D.S., Bingol B., Corn J.E.; RT "USP30 and parkin homeostatically regulate atypical ubiquitin chains on RT mitochondria."; RL Nat. Cell Biol. 17:160-169(2015). RN [61] RP FUNCTION, ISGYLATION OF LYS-349 AND LYS-369, AND ACTIVITY REGULATION. RX PubMed=27534820; DOI=10.1098/rsob.160193; RA Im E., Yoo L., Hyun M., Shin W.H., Chung K.C.; RT "Covalent ISG15 conjugation positively regulates the ubiquitin E3 ligase RT activity of parkin."; RL Open Biol. 6:0-0(2016). RN [62] RP FUNCTION, MUTAGENESIS OF CYS-431, AND CHARACTERIZATION OF VARIANT PARK2 RP ASN-415. RX PubMed=32047033; DOI=10.1073/pnas.1909814117; RA Ham S.J., Lee D., Yoo H., Jun K., Shin H., Chung J.; RT "Decision between mitophagy and apoptosis by Parkin via VDAC1 RT ubiquitination."; RL Proc. Natl. Acad. Sci. U.S.A. 117:4281-4291(2020). RN [63] RP FUNCTION. RX PubMed=33499712; DOI=10.1080/15548627.2021.1874133; RA Kojima W., Yamano K., Kosako H., Imai K., Kikuchi R., Tanaka K., RA Matsuda N.; RT "Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site RT in response to selective and non-selective autophagy."; RL Autophagy 1:1-26(2021). RN [64] RP STRUCTURE BY NMR OF 1-76, AND INTERACTION WITH PSMD4. RX PubMed=12634850; DOI=10.1038/sj.embor.embor764; RA Sakata E., Yamaguchi Y., Kurimoto E., Kikuchi J., Yokoyama S., Yamada S., RA Kawahara H., Yokosawa H., Hattori N., Mizuno Y., Tanaka K., Kato K.; RT "Parkin binds the Rpn10 subunit of 26S proteasomes through its ubiquitin- RT like domain."; RL EMBO Rep. 4:301-306(2003). RN [65] RP STRUCTURE BY NMR OF 307-384 IN COMPLEX WITH ZINC IONS, CHARACTERIZATION OF RP VARIANT PARK2 PRO-351, MUTAGENESIS OF CYS-332 AND CYS-365, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=17360614; DOI=10.1073/pnas.0610548104; RA Beasley S.A., Hristova V.A., Shaw G.S.; RT "Structure of the Parkin in-between-ring domain provides insights for E3- RT ligase dysfunction in autosomal recessive Parkinson's disease."; RL Proc. Natl. Acad. Sci. U.S.A. 104:3095-3100(2007). RN [66] RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 137-465, ACTIVITY REGULATION, AND RP MUTAGENESIS OF CYS-431; HIS-433 AND GLU-444. RX PubMed=23727886; DOI=10.1038/emboj.2013.125; RA Wauer T., Komander D.; RT "Structure of the human Parkin ligase domain in an autoinhibited state."; RL EMBO J. 32:2099-2112(2013). RN [67] RP X-RAY CRYSTALLOGRAPHY (1.58 ANGSTROMS) OF 137-465, ACTIVE SITE, CATALYTIC RP ACTIVITY, ACTIVITY REGULATION, AND MUTAGENESIS OF CYS-431; HIS-433 AND RP GLU-444. RX PubMed=23770887; DOI=10.1038/ncomms2982; RA Riley B.E., Lougheed J.C., Callaway K., Velasquez M., Brecht E., Nguyen L., RA Shaler T., Walker D., Yang Y., Regnstrom K., Diep L., Zhang Z., Chiou S., RA Bova M., Artis D.R., Yao N., Baker J., Yednock T., Johnston J.A.; RT "Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RT RING and HECT ligases."; RL Nat. Commun. 4:1982-1982(2013). RN [68] RP REVIEW ON VARIANTS. RX PubMed=14976155; DOI=10.1093/hmg/ddh089; RA Mata I.F., Lockhart P.J., Farrer M.J.; RT "Parkin genetics: one model for Parkinson's disease."; RL Hum. Mol. Genet. 13:R127-R133(2004). RN [69] RP VARIANT PARK2 ARG-240. RX PubMed=9731209; DOI=10.1006/bbrc.1998.9134; RA Hattori N., Matsumine H., Asakawa S., Kitada T., Yoshino H., Elibol B., RA Brookes A.J., Yamamura Y., Kobayashi T., Wang M., Yoritaka A., RA Minoshima S., Shimizu N., Mizuno Y.; RT "Point mutations (Thr240Arg and Gln311Stop) in the Parkin gene."; RL Biochem. Biophys. Res. Commun. 249:754-758(1998). RN [70] RP ERRATUM OF PUBMED:9731209. RA Hattori N., Matsumine H., Asakawa S., Kitada T., Yoshino H., Elibol B., RA Brookes A.J., Yamamura Y., Kobayashi T., Wang M., Yoritaka A., RA Minoshima S., Shimizu N., Mizuno Y.; RL Biochem. Biophys. Res. Commun. 251:666-666(1998). RN [71] RP VARIANTS PARK2 ASN-161; CYS-256; TRP-275 AND ASN-415, AND VARIANTS ASN-167; RP LEU-380 AND ASN-394. RX PubMed=10072423; DOI=10.1093/hmg/8.4.567; RA Abbas N., Luecking C.B., Ricard S., Duerr A., Bonifati V., De Michele G., RA Bouley S., Vaughan J.R., Gasser T., Marconi R., Broussolle E., RA Brefel-Courbon C., Harhangi B.S., Oostra B.A., Fabrizio E., Bohme G.A., RA Pradier L., Wood N.W., Filla A., Meco G., Denefle P., Agid Y., Brice A.; RT "A wide variety of mutations in the parkin gene are responsible for RT autosomal recessive parkinsonism in Europe."; RL Hum. Mol. Genet. 8:567-574(1999). RN [72] RP VARIANT ASN-167. RX PubMed=10511432; DOI=10.1097/00001756-199909090-00008; RA Satoh J., Kuroda Y.; RT "Association of codon 167 Ser/Asn heterozygosity in the parkin gene with RT sporadic Parkinson's disease."; RL NeuroReport 10:2735-2739(1999). RN [73] RP VARIANT PARK2 PHE-431. RX PubMed=10939576; RX DOI=10.1002/1531-8249(200008)48:2<245::aid-ana15>3.3.co;2-u; RA Maruyama M., Ikeuchi T., Saito M., Ishikawa A., Yuasa T., Tanaka H., RA Hayashi S., Wakabayashi K., Takahashi H., Tsuji S.; RT "Novel mutations, pseudo-dominant inheritance, and possible familial RT affects in patients with autosomal recessive juvenile parkinsonism."; RL Ann. Neurol. 48:245-250(2000). RN [74] RP VARIANTS ASN-167; TRP-366 AND LEU-380. RX PubMed=10965160; DOI=10.1159/000008203; RA Hu C.-J., Sung S.-M., Liu H.-C., Lee C.-C., Tsai C.-H., Chang J.-G.; RT "Polymorphisms of the parkin gene in sporadic Parkinson's disease among RT Chinese in Taiwan."; RL Eur. Neurol. 44:90-93(2000). RN [75] RP VARIANTS PARK2 ASN-161; ASN-211; CYS-256; TRP-275; ASN-280; GLY-289; RP GLU-328; ASN-415 AND ASP-430, AND VARIANT CYS-334. RX PubMed=10824074; DOI=10.1056/nejm200005253422103; RA Luecking C.B., Duerr A., Bonifati V., Vaughan J.R., De Michele G., RA Gasser T., Harhangi B.S., Meco G., Denefle P., Wood N.W., Agid Y., RA Brice A.; RT "Association between early-onset Parkinson's disease and mutations in the RT parkin gene."; RL N. Engl. J. Med. 342:1560-1567(2000). RN [76] RP VARIANTS PARK2 ASN-211; TRP-275 AND ASP-430. RX PubMed=11179010; DOI=10.1086/318791; RA Periquet M., Luecking C.B., Vaughan J.R., Bonifati V., Duerr A., RA De Michele G., Horstink M., Farrer M., Illarioshkin S.N., Pollak P., RA Borg M., Brefel-Courbon C., Denefle P., Meco G., Gasser T., Breteler M.M., RA Wood N.W., Agid Y., Brice A.; RT "Origin of the mutations in the parkin gene in Europe: exon rearrangements RT are independent recurrent events, whereas point mutations may result from RT founder effects."; RL Am. J. Hum. Genet. 68:617-626(2001). RN [77] RP VARIANT PARK2 GLU-82. RX PubMed=11487568; DOI=10.1093/hmg/10.16.1649; RA Hedrich K., Kann M., Lanthaler A.J., Dalski A., Eskelson C., Landt O., RA Schwinger E., Vieregge P., Lang A.E., Breakefield X.O., Ozelius L.J., RA Pramstaller P.P., Klein C.; RT "The importance of gene dosage studies: mutational analysis of the parkin RT gene in early-onset parkinsonism."; RL Hum. Mol. Genet. 10:1649-1656(2001). RN [78] RP VARIANT PARK2 TYR-212. RX PubMed=11163284; DOI=10.1016/s0304-3940(00)01733-x; RA Pineda-Trujillo N., Carvajal-Carmona L.G., Buritica O., Moreno S., RA Uribe C., Pineda D., Toro M., Garcia F., Arias W., Bedoya G., Lopera F., RA Ruiz-Linares A.; RT "A novel Cys212Tyr founder mutation in parkin and allelic heterogeneity of RT juvenile parkinsonism in a population from North West Colombia."; RL Neurosci. Lett. 298:87-90(2001). RN [79] RP VARIANTS PARK2 GLU-82; CYS-256; TRP-275; GLU-328 AND ARG-441. RX PubMed=12116199; DOI=10.1002/ajmg.10525; RG French Parkinson's disease genetics study group; RG European consortium on genetic susceptibility on Parkinson's disease; RA West A., Periquet M., Lincoln S., Luecking C.B., Nicholl D., Bonifati V., RA Rawal N., Gasser T., Lohmann E., Deleuze J.-F., Maraganore D., Levey A., RA Wood N.W., Duerr A., Hardy J., Brice A., Farrer M.; RT "Complex relationship between parkin mutations and Parkinson disease."; RL Am. J. Med. Genet. 114:584-591(2002). RN [80] RP ERRATUM OF PUBMED:12116199. RG French Parkinson's disease genetics study group; RG European consortium on genetic susceptibility on Parkinson's disease; RA West A., Periquet M., Lincoln S., Luecking C.B., Nicholl D., Bonifati V., RA Rawal N., Gasser T., Lohmann E., Deleuze J.-F., Maraganore D., Levey A., RA Wood N.W., Duerr A., Hardy J., Brice A., Farrer M.J.; RL Am. J. Med. Genet. 114:992-992(2002). RN [81] RP VARIANTS PARK2 LEU-37 AND PRO-351. RX PubMed=12112109; DOI=10.1002/ana.10179; RA Kann M., Jacobs H., Mohrmann K., Schumacher K., Hedrich K., Garrels J., RA Wiegers K., Schwinger E., Pramstaller P.P., Breakefield X.O., Ozelius L.J., RA Vieregge P., Klein C.; RT "Role of parkin mutations in 111 community-based patients with early-onset RT parkinsonism."; RL Ann. Neurol. 51:621-625(2002). RN [82] RP VARIANTS PARK2 GLU-56 AND TYR-212. RX PubMed=12056932; DOI=10.1001/archneur.59.6.966; RA Hoenicka J., Vidal L., Morales B., Ampuero I., Jimenez-Jimenez F.J., RA Berciano J., del Ser T., Jimenez A., Ruiz P.G., de Yebenes J.G.; RT "Molecular findings in familial Parkinson disease in Spain."; RL Arch. Neurol. 59:966-970(2002). RN [83] RP VARIANTS PARK2 ASN-211; TRP-275; ASP-430 AND LEU-437. RX PubMed=12114481; DOI=10.1136/jmg.39.7.489; RA Nichols W.C., Pankratz N., Uniacke S.K., Pauciulo M.W., Halter C., RA Rudolph A., Conneally P.M., Foroud T.; RT "Linkage stratification and mutation analysis at the parkin locus RT identifies mutation positive Parkinson's disease families."; RL J. Med. Genet. 39:489-492(2002). RN [84] RP VARIANT PARK2 MET-15, AND VARIANTS LEU-380 AND ASN-394. RX PubMed=12397156; DOI=10.1136/jnnp.73.5.582; RA Munoz E., Tolosa E., Pastor P., Marti M.J., Valldeoriola F., RA Campdelacreu J., Oliva R.; RT "Relative high frequency of the c.255delA parkin gene mutation in Spanish RT patients with autosomal recessive parkinsonism."; RL J. Neurol. Neurosurg. Psych. 73:582-584(2002). RN [85] RP VARIANTS PARK2 PRO-42; LEU-192; CYS-256; TRP-275; ASP-430 AND LEU-437. RX PubMed=11971093; DOI=10.1212/wnl.58.8.1239; RA Hedrich K., Marder K., Harris J., Kann M., Lynch T., Meija-Santana H., RA Pramstaller P.P., Schwinger E., Bressman S.B., Fahn S., Klein C.; RT "Evaluation of 50 probands with early-onset Parkinson's disease for parkin RT mutations."; RL Neurology 58:1239-1246(2002). RN [86] RP VARIANT PARK2 PRO-46. RX PubMed=12362318; RA Xu Y., Liu Z., Wang Y., Tao E., Chen G., Chen B.; RT "A new point mutation on exon 2 of parkin gene in Parkinson's disease."; RL Zhonghua Yi Xue Yi Chuan Xue Za Zhi 19:409-411(2002). RN [87] RP VARIANTS PARK2 GLN-33; GLU-82; ASP-430 AND LEU-437, VARIANTS PARK TYR-253; RP CYS-256; TRP-275 AND ASN-280, AND VARIANTS LEU-380 AND ASN-394. RX PubMed=12730996; DOI=10.1002/ana.10524; RA Oliveira S.A., Scott W.K., Martin E.R., Nance M.A., Watts R.L., RA Hubble J.P., Koller W.C., Pahwa R., Stern M.B., Hiner B.C., Ondo W.G., RA Allen F.H. Jr., Scott B.L., Goetz C.G., Small G.W., Mastaglia F., RA Stajich J.M., Zhang F., Booze M.W., Winn M.P., Middleton L.T., Haines J.L., RA Pericak-Vance M.A., Vance J.M.; RT "Parkin mutations and susceptibility alleles in late-onset Parkinson's RT disease."; RL Ann. Neurol. 53:624-629(2003). RN [88] RP VARIANTS PARK2 VAL-192; ASN-211; MET-240 AND LEU-437, VARIANT ASN-167, AND RP INVOLVEMENT IN LATE-ONSET PARK. RX PubMed=12629236; DOI=10.1212/01.wnl.0000049470.00180.07; RA Foroud T., Uniacke S.K., Liu L., Pankratz N., Rudolph A., Halter C., RA Shults C., Marder K., Conneally P.M., Nichols W.C.; RT "Heterozygosity for a mutation in the parkin gene leads to later onset RT Parkinson disease."; RL Neurology 60:796-801(2003). RN [89] RP VARIANTS HIS-100; SER-271 AND SER-339. RX PubMed=12781599; DOI=10.1016/s1353-8020(03)00018-x; RA Chen R., Gosavi N.S., Langston J.W., Chan P.; RT "Parkin mutations are rare in patients with young-onset parkinsonism in a RT US population."; RL Parkinsonism Relat. Disord. 9:309-312(2003). RN [90] RP VARIANTS PARK2 PRO-42; CYS-402; ASN-415 AND ARG-418. RX PubMed=15584030; DOI=10.1002/mds.20343; RG Italian Parkinson Genetics Network; RA Bertoli-Avella A.M., Giroud-Benitez J.L., Akyol A., Barbosa E., Schaap O., RA van der Linde H.C., Martignoni E., Lopiano L., Lamberti P., Fincati E., RA Antonini A., Stocchi F., Montagna P., Squitieri F., Marini P., RA Abbruzzese G., Fabbrini G., Marconi R., Dalla Libera A., Trianni G., RA Guidi M., De Gaetano A., Boff Maegawa G., De Leo A., Gallai V., de Rosa G., RA Vanacore N., Meco G., van Duijn C.M., Oostra B.A., Heutink P., Bonifati V.; RT "Novel parkin mutations detected in patients with early-onset Parkinson's RT disease."; RL Mov. Disord. 20:424-431(2005). RN [91] RP CHARACTERIZATION OF VARIANTS PARK2 ASN-161; ASN-211; ARG-240; ASN-280 AND RP GLU-328. RX PubMed=20404107; DOI=10.1083/jcb.200910140; RA Matsuda N., Sato S., Shiba K., Okatsu K., Saisho K., Gautier C.A., RA Sou Y.S., Saiki S., Kawajiri S., Sato F., Kimura M., Komatsu M., RA Hattori N., Tanaka K.; RT "PINK1 stabilized by mitochondrial depolarization recruits Parkin to RT damaged mitochondria and activates latent Parkin for mitophagy."; RL J. Cell Biol. 189:211-221(2010). RN [92] RP VARIANT PARK2 TRP-275. RX PubMed=22956510; DOI=10.1002/mds.25132; RA Kilarski L.L., Pearson J.P., Newsway V., Majounie E., Knipe M.D., RA Misbahuddin A., Chinnery P.F., Burn D.J., Clarke C.E., Marion M.H., RA Lewthwaite A.J., Nicholl D.J., Wood N.W., Morrison K.E., RA Williams-Gray C.H., Evans J.R., Sawcer S.J., Barker R.A., RA Wickremaratchi M.M., Ben-Shlomo Y., Williams N.M., Morris H.R.; RT "Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ- RT 1) and LRRK2 in early-onset Parkinson's disease."; RL Mov. Disord. 27:1522-1529(2012). RN [93] RP VARIANT CYS-334. RX PubMed=27535533; DOI=10.1038/nature19057; RG Exome Aggregation Consortium; RA Lek M., Karczewski K.J., Minikel E.V., Samocha K.E., Banks E., Fennell T., RA O'Donnell-Luria A.H., Ware J.S., Hill A.J., Cummings B.B., Tukiainen T., RA Birnbaum D.P., Kosmicki J.A., Duncan L.E., Estrada K., Zhao F., Zou J., RA Pierce-Hoffman E., Berghout J., Cooper D.N., Deflaux N., DePristo M., RA Do R., Flannick J., Fromer M., Gauthier L., Goldstein J., Gupta N., RA Howrigan D., Kiezun A., Kurki M.I., Moonshine A.L., Natarajan P., RA Orozco L., Peloso G.M., Poplin R., Rivas M.A., Ruano-Rubio V., Rose S.A., RA Ruderfer D.M., Shakir K., Stenson P.D., Stevens C., Thomas B.P., Tiao G., RA Tusie-Luna M.T., Weisburd B., Won H.H., Yu D., Altshuler D.M., RA Ardissino D., Boehnke M., Danesh J., Donnelly S., Elosua R., Florez J.C., RA Gabriel S.B., Getz G., Glatt S.J., Hultman C.M., Kathiresan S., Laakso M., RA McCarroll S., McCarthy M.I., McGovern D., McPherson R., Neale B.M., RA Palotie A., Purcell S.M., Saleheen D., Scharf J.M., Sklar P., RA Sullivan P.F., Tuomilehto J., Tsuang M.T., Watkins H.C., Wilson J.G., RA Daly M.J., MacArthur D.G.; RT "Analysis of protein-coding genetic variation in 60,706 humans."; RL Nature 536:285-291(2016). RN [94] RP CHARACTERIZATION OF VARIANTS PARK PRO-42 AND TRP-275, AND FUNCTION. RX PubMed=29311685; DOI=10.1038/s41467-017-02593-y; RA Wang C., Kang X., Zhou L., Chai Z., Wu Q., Huang R., Xu H., Hu M., Sun X., RA Sun S., Li J., Jiao R., Zuo P., Zheng L., Yue Z., Zhou Z.; RT "Synaptotagmin-11 is a critical mediator of parkin-linked neurotoxicity and RT Parkinson's disease-like pathology."; RL Nat. Commun. 9:81-81(2018). CC -!- FUNCTION: Functions within a multiprotein E3 ubiquitin ligase complex, CC catalyzing the covalent attachment of ubiquitin moieties onto substrate CC proteins (PubMed:10888878, PubMed:10973942, PubMed:11431533, CC PubMed:12150907, PubMed:12628165, PubMed:15105460, PubMed:16135753, CC PubMed:21376232, PubMed:21532592, PubMed:22396657, PubMed:23620051, CC PubMed:23754282, PubMed:24660806, PubMed:24751536, PubMed:29311685, CC PubMed:32047033). Substrates include SYT11 and VDAC1 (PubMed:29311685, CC PubMed:32047033). Other substrates are BCL2, CCNE1, GPR37, RHOT1/MIRO1, CC MFN1, MFN2, STUB1, SNCAIP, SEPTIN5, TOMM20, USP30, ZNF746, MIRO1 and CC AIMP2 (PubMed:10888878, PubMed:10973942, PubMed:11431533, CC PubMed:12150907, PubMed:12628165, PubMed:15105460, PubMed:16135753, CC PubMed:21376232, PubMed:21532592, PubMed:22396657, PubMed:23620051, CC PubMed:23754282, PubMed:24660806, PubMed:24751536). Mediates CC monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and CC 'Lys-63'-linked polyubiquitination of substrates depending on the CC context (PubMed:19229105, PubMed:20889974, PubMed:25474007, CC PubMed:25621951, PubMed:32047033). Participates in the removal and/or CC detoxification of abnormally folded or damaged protein by mediating CC 'Lys-63'-linked polyubiquitination of misfolded proteins such as PARK7: CC 'Lys-63'-linked polyubiquitinated misfolded proteins are then CC recognized by HDAC6, leading to their recruitment to aggresomes, CC followed by degradation (PubMed:17846173, PubMed:19229105). Mediates CC 'Lys-63'-linked polyubiquitination of a 22 kDa O-linked glycosylated CC isoform of SNCAIP, possibly playing a role in Lewy-body formation CC (PubMed:11431533, PubMed:11590439, PubMed:15105460, PubMed:15728840, CC PubMed:19229105). Mediates monoubiquitination of BCL2, thereby acting CC as a positive regulator of autophagy (PubMed:20889974). Protects CC against mitochondrial dysfunction during cellular stress, by acting CC downstream of PINK1 to coordinate mitochondrial quality control CC mechanisms that remove and replace dysfunctional mitochondrial CC components (PubMed:11439185, PubMed:18957282, PubMed:19029340, CC PubMed:19966284, PubMed:21376232, PubMed:22082830, PubMed:22396657, CC PubMed:23620051, PubMed:23933751, PubMed:24660806, PubMed:24784582, CC PubMed:24896179, PubMed:25474007, PubMed:25527291, PubMed:32047033). CC Depending on the severity of mitochondrial damage and/or dysfunction, CC activity ranges from preventing apoptosis and stimulating mitochondrial CC biogenesis to regulating mitochondrial dynamics and eliminating CC severely damaged mitochondria via mitophagy (PubMed:11439185, CC PubMed:19029340, PubMed:19801972, PubMed:19966284, PubMed:21376232, CC PubMed:22082830, PubMed:22396657, PubMed:23620051, PubMed:23685073, CC PubMed:23933751, PubMed:24896179, PubMed:25527291, PubMed:32047033, CC PubMed:33499712). Activation and recruitment onto the outer membrane of CC damaged/dysfunctional mitochondria (OMM) requires PINK1-mediated CC phosphorylation of both PRKN and ubiquitin (PubMed:24660806, CC PubMed:24784582, PubMed:25474007, PubMed:25527291). After mitochondrial CC damage, functions with PINK1 to mediate the decision between mitophagy CC or preventing apoptosis by inducing either the poly- or CC monoubiquitination of VDAC1, respectively; polyubiquitination of VDAC1 CC promotes mitophagy, while monoubiquitination of VDAC1 decreases CC mitochondrial calcium influx which ultimately inhibits apoptosis CC (PubMed:27534820, PubMed:32047033). When cellular stress results in CC irreversible mitochondrial damage, promotes the autophagic degradation CC of dysfunctional depolarized mitochondria (mitophagy) by promoting the CC ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1, CC MFN1 and USP30 (PubMed:19029340, PubMed:19966284, PubMed:21753002, CC PubMed:22396657, PubMed:23620051, PubMed:23685073, PubMed:23933751, CC PubMed:24896179, PubMed:25527291). Preferentially assembles 'Lys-6'-, CC 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains, leading to CC mitophagy (PubMed:25621951, PubMed:32047033). The PINK1-PRKN pathway CC also promotes fission of damaged mitochondria by PINK1-mediated CC phosphorylation which promotes the PRKN-dependent degradation of CC mitochondrial proteins involved in fission such as MFN2 CC (PubMed:23620051). This prevents the refusion of unhealthy mitochondria CC with the mitochondrial network or initiates mitochondrial fragmentation CC facilitating their later engulfment by autophagosomes CC (PubMed:23620051). Regulates motility of damaged mitochondria via the CC ubiquitination and subsequent degradation of MIRO1 and MIRO2; in motor CC neurons, this likely inhibits mitochondrial intracellular anterograde CC transport along the axons which probably increases the chance of the CC mitochondria undergoing mitophagy in the soma (PubMed:22396657). CC Involved in mitochondrial biogenesis via the 'Lys-48'-linked CC polyubiquitination of transcriptional repressor ZNF746/PARIS which CC leads to its subsequent proteasomal degradation and allows activation CC of the transcription factor PPARGC1A (PubMed:21376232). Limits the CC production of reactive oxygen species (ROS) (PubMed:18541373). CC Regulates cyclin-E during neuronal apoptosis (PubMed:12628165). In CC collaboration with CHPF isoform 2, may enhance cell viability and CC protect cells from oxidative stress (PubMed:22082830). Independently of CC its ubiquitin ligase activity, protects from apoptosis by the CC transcriptional repression of p53/TP53 (PubMed:19801972). May protect CC neurons against alpha synuclein toxicity, proteasomal dysfunction, CC GPR37 accumulation, and kainate-induced excitotoxicity CC (PubMed:11439185). May play a role in controlling neurotransmitter CC trafficking at the presynaptic terminal and in calcium-dependent CC exocytosis. May represent a tumor suppressor gene (PubMed:12719539). CC {ECO:0000269|PubMed:10888878, ECO:0000269|PubMed:10973942, CC ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11439185, CC ECO:0000269|PubMed:11590439, ECO:0000269|PubMed:12150907, CC ECO:0000269|PubMed:12628165, ECO:0000269|PubMed:12719539, CC ECO:0000269|PubMed:15105460, ECO:0000269|PubMed:15728840, CC ECO:0000269|PubMed:16135753, ECO:0000269|PubMed:17846173, CC ECO:0000269|PubMed:18541373, ECO:0000269|PubMed:18957282, CC ECO:0000269|PubMed:19029340, ECO:0000269|PubMed:19229105, CC ECO:0000269|PubMed:19801972, ECO:0000269|PubMed:19966284, CC ECO:0000269|PubMed:20889974, ECO:0000269|PubMed:21376232, CC ECO:0000269|PubMed:21532592, ECO:0000269|PubMed:21753002, CC ECO:0000269|PubMed:22082830, ECO:0000269|PubMed:22396657, CC ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:23685073, CC ECO:0000269|PubMed:23754282, ECO:0000269|PubMed:23933751, CC ECO:0000269|PubMed:24660806, ECO:0000269|PubMed:24751536, CC ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:24896179, CC ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:25527291, CC ECO:0000269|PubMed:25621951, ECO:0000269|PubMed:27534820, CC ECO:0000269|PubMed:29311685, ECO:0000269|PubMed:32047033, CC ECO:0000269|PubMed:33499712}. CC -!- CATALYTIC ACTIVITY: CC Reaction=[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- CC cysteine + [acceptor protein]-N(6)-ubiquitinyl-L-lysine.; CC EC=2.3.2.31; Evidence={ECO:0000269|PubMed:23770887}; CC -!- ACTIVITY REGULATION: In the autoinhibited state the side chain of Phe- CC 463 inserts into a hydrophobic groove in RING-0, occluding the CC ubiquitin acceptor site Cys-431, whereas the REP repressor element CC binds RING-1 and blocks its E2-binding site (PubMed:23727886, CC PubMed:23770887). Activation of PRKN requires 2 steps: (1) CC phosphorylation at Ser-65 by PINK1 and (2) binding to phosphorylated CC ubiquitin, leading to unlock repression of the catalytic Cys-431 by the CC RING-0 region via an allosteric mechanism and converting PRKN to its CC fully-active form (PubMed:24660806, PubMed:24784582, PubMed:25474007, CC PubMed:25527291). According to another report, phosphorylation at Ser- CC 65 by PINK1 is not essential for activation and only binding to CC phosphorylated ubiquitin is essential to unlock repression CC (PubMed:24751536). In addition, ISG15 conjugation positively regulates CC its ubiquitin E3 ligase activity by suppressing the intramolecular CC interaction that maintains its autoinhibited conformation CC (PubMed:27534820). {ECO:0000269|PubMed:23727886, CC ECO:0000269|PubMed:23770887, ECO:0000269|PubMed:24660806, CC ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582, CC ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:25527291, CC ECO:0000269|PubMed:27534820}. CC -!- PATHWAY: Protein modification; protein ubiquitination. CC -!- SUBUNIT: Forms an E3 ubiquitin ligase complex with UBE2L3 or UBE2L6 CC (PubMed:11078524, PubMed:21532592). Mediates 'Lys-63'-linked CC polyubiquitination by associating with UBE2V1. Part of a SCF-like CC complex, consisting of PRKN, CUL1 and FBXW7 (PubMed:12628165). CC Interacts with SNCAIP (PubMed:11590439, PubMed:15728840). Binds to the CC C2A and C2B domains of SYT11 (PubMed:12925569). Interacts and regulates CC the turnover of SEPTIN5 (PubMed:11078524). Part of a complex, including CC STUB1, HSP70 and GPR37 (PubMed:12150907). The amount of STUB1 in the CC complex increases during ER stress (PubMed:12150907). STUB1 promotes CC the dissociation of HSP70 from PRKN and GPR37, thus facilitating PRKN- CC mediated GPR37 ubiquitination (PubMed:12150907). HSP70 transiently CC associates with unfolded GPR37 and inhibits the E3 activity of PRKN, CC whereas, STUB1 enhances the E3 activity of PRKN through promotion of CC dissociation of HSP70 from PRKN-GPR37 complexes (PubMed:12150907). CC Interacts with PSMD4 and PACRG (PubMed:12634850, PubMed:14532270). CC Interacts with LRRK2 (PubMed:16352719). Interacts with RANBP2 CC (PubMed:16332688). Interacts with SUMO1 but not SUMO2, which promotes CC nuclear localization and autoubiquitination (PubMed:16955485). CC Interacts (via first RING-type domain) with AIMP2 (via N-terminus) CC (PubMed:16135753). Interacts with PSMA7 and RNF41 (PubMed:15987638, CC PubMed:18541373). Interacts with PINK1 (PubMed:19966284, CC PubMed:20798600). Forms a complex with PINK1 and PARK7 CC (PubMed:19229105). Interacts with CHPF, the interaction with isoform 2 CC may facilitate PRKN transport into the mitochondria (PubMed:22082830). CC Interacts with MFN2 (phosphorylated), promotes PRKN localization in CC dysfunctional depolarized mitochondria (PubMed:23620051). Interacts CC with FBXO7; this promotes translocation to dysfunctional depolarized CC mitochondria (PubMed:23933751). Interacts with ZNF746 CC (PubMed:21376232). Interacts with heat shock protein 70 family members, CC including HSPA1L, HSPA1A and HSPA8; interaction HSPA1L promotes CC translocation to damaged mitochondria (PubMed:24270810). Interacts with CC BAG4 and, to a lesser extent, BAG5; interaction with BAG4 inhibits CC translocation to damaged mitochondria (PubMed:24270810). Forms a CC complex with PRKN and PARK7 (PubMed:19229105). Interacts with AMBRA1 CC (By similarity). {ECO:0000250|UniProtKB:Q9WVS6, CC ECO:0000269|PubMed:11078524, ECO:0000269|PubMed:11590439, CC ECO:0000269|PubMed:12150907, ECO:0000269|PubMed:12628165, CC ECO:0000269|PubMed:12634850, ECO:0000269|PubMed:12925569, CC ECO:0000269|PubMed:14532270, ECO:0000269|PubMed:15728840, CC ECO:0000269|PubMed:15987638, ECO:0000269|PubMed:16135753, CC ECO:0000269|PubMed:16332688, ECO:0000269|PubMed:16352719, CC ECO:0000269|PubMed:16955485, ECO:0000269|PubMed:18541373, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19966284, CC ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:21376232, CC ECO:0000269|PubMed:21532592, ECO:0000269|PubMed:22082830, CC ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:23933751, CC ECO:0000269|PubMed:24270810}. CC -!- INTERACTION: CC O60260; P54252-2: ATXN3; NbExp=5; IntAct=EBI-716346, EBI-9684323; CC O60260; Q8IZ52-2: CHPF; NbExp=5; IntAct=EBI-716346, EBI-9029620; CC O60260; Q9Y3I1: FBXO7; NbExp=10; IntAct=EBI-716346, EBI-1161222; CC O60260; Q9Y3I1-1: FBXO7; NbExp=2; IntAct=EBI-716346, EBI-9102965; CC O60260; Q9UBN7: HDAC6; NbExp=6; IntAct=EBI-716346, EBI-301697; CC O60260; P08238: HSP90AB1; NbExp=2; IntAct=EBI-716346, EBI-352572; CC O60260; Q8TBB1: LNX1; NbExp=3; IntAct=EBI-716346, EBI-739832; CC O60260; Q5S007: LRRK2; NbExp=3; IntAct=EBI-716346, EBI-5323863; CC O60260; Q86UL8: MAGI2; NbExp=2; IntAct=EBI-716346, EBI-311035; CC O60260; O95140: MFN2; NbExp=4; IntAct=EBI-716346, EBI-3324756; CC O60260; Q16342: PDCD2; NbExp=5; IntAct=EBI-716346, EBI-359462; CC O60260; Q9BXM7: PINK1; NbExp=7; IntAct=EBI-716346, EBI-2846068; CC O60260; Q9BXM7-1: PINK1; NbExp=2; IntAct=EBI-716346, EBI-15643376; CC O60260; O60260: PRKN; NbExp=5; IntAct=EBI-716346, EBI-716346; CC O60260; O14818-1: PSMA7; NbExp=5; IntAct=EBI-716346, EBI-7679034; CC O60260; P49792: RANBP2; NbExp=11; IntAct=EBI-716346, EBI-973138; CC O60260; Q8IXI2: RHOT1; NbExp=3; IntAct=EBI-716346, EBI-1396430; CC O60260; Q15645: TRIP13; NbExp=4; IntAct=EBI-716346, EBI-358993; CC O60260; Q6NUN9: ZNF746; NbExp=6; IntAct=EBI-716346, EBI-3862525; CC O60260; Q9Z2Q6: Septin5; Xeno; NbExp=2; IntAct=EBI-716346, EBI-772125; CC O60260; P68510: Ywhah; Xeno; NbExp=6; IntAct=EBI-716346, EBI-444641; CC O60260; PRO_0000045592 [Q99IB8]; Xeno; NbExp=3; IntAct=EBI-716346, EBI-6858513; CC O60260-5; Q6ZTN6-2: ANKRD13D; NbExp=3; IntAct=EBI-21251460, EBI-25840993; CC O60260-5; Q86WR3: ANUBL1; NbExp=3; IntAct=EBI-21251460, EBI-25880850; CC O60260-5; P63010-2: AP2B1; NbExp=6; IntAct=EBI-21251460, EBI-11529439; CC O60260-5; P05067: APP; NbExp=5; IntAct=EBI-21251460, EBI-77613; CC O60260-5; Q0P5N6: ARL16; NbExp=6; IntAct=EBI-21251460, EBI-10186132; CC O60260-5; Q86TN1: ARNT2; NbExp=3; IntAct=EBI-21251460, EBI-25844820; CC O60260-5; Q8WXK3: ASB13; NbExp=3; IntAct=EBI-21251460, EBI-707573; CC O60260-5; Q8WXK3-2: ASB13; NbExp=3; IntAct=EBI-21251460, EBI-12015080; CC O60260-5; Q9Y575-3: ASB3; NbExp=3; IntAct=EBI-21251460, EBI-14199987; CC O60260-5; Q9H672-2: ASB7; NbExp=3; IntAct=EBI-21251460, EBI-12104328; CC O60260-5; Q96DX5: ASB9; NbExp=3; IntAct=EBI-21251460, EBI-745641; CC O60260-5; Q96DX5-3: ASB9; NbExp=3; IntAct=EBI-21251460, EBI-25843552; CC O60260-5; Q9H0Y0: ATG10; NbExp=3; IntAct=EBI-21251460, EBI-1048913; CC O60260-5; P54253: ATXN1; NbExp=6; IntAct=EBI-21251460, EBI-930964; CC O60260-5; O14867: BACH1; NbExp=3; IntAct=EBI-21251460, EBI-1263541; CC O60260-5; P46379-2: BAG6; NbExp=3; IntAct=EBI-21251460, EBI-10988864; CC O60260-5; A8KA13: BCL6B; NbExp=3; IntAct=EBI-21251460, EBI-10174813; CC O60260-5; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-21251460, EBI-2837444; CC O60260-5; P29466-3: CASP1; NbExp=6; IntAct=EBI-21251460, EBI-12248206; CC O60260-5; Q13939: CCIN; NbExp=3; IntAct=EBI-21251460, EBI-25879469; CC O60260-5; P78396-2: CCNA1; NbExp=3; IntAct=EBI-21251460, EBI-21770675; CC O60260-5; Q00535: CDK5; NbExp=3; IntAct=EBI-21251460, EBI-1041567; CC O60260-5; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-21251460, EBI-350590; CC O60260-5; Q9UBU7: DBF4; NbExp=3; IntAct=EBI-21251460, EBI-372690; CC O60260-5; Q5QP82-2: DCAF10; NbExp=3; IntAct=EBI-21251460, EBI-10983996; CC O60260-5; P61962: DCAF7; NbExp=3; IntAct=EBI-21251460, EBI-359808; CC O60260-5; Q5TAQ9-2: DCAF8; NbExp=3; IntAct=EBI-21251460, EBI-25842815; CC O60260-5; Q9BW61: DDA1; NbExp=3; IntAct=EBI-21251460, EBI-2510241; CC O60260-5; Q8NDP9: DKFZp547K2416; NbExp=3; IntAct=EBI-21251460, EBI-25842538; CC O60260-5; P78352-2: DLG4; NbExp=6; IntAct=EBI-21251460, EBI-631152; CC O60260-5; P31689: DNAJA1; NbExp=6; IntAct=EBI-21251460, EBI-347834; CC O60260-5; O77932: DXO; NbExp=3; IntAct=EBI-21251460, EBI-372173; CC O60260-5; O75530-2: EED; NbExp=3; IntAct=EBI-21251460, EBI-11132357; CC O60260-5; Q8TC29: ENKUR; NbExp=6; IntAct=EBI-21251460, EBI-9246952; CC O60260-5; Q6P1L5: FAM117B; NbExp=3; IntAct=EBI-21251460, EBI-3893327; CC O60260-5; O00757: FBP2; NbExp=3; IntAct=EBI-21251460, EBI-719781; CC O60260-5; P57775: FBXW4; NbExp=3; IntAct=EBI-21251460, EBI-2372268; CC O60260-5; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-21251460, EBI-396453; CC O60260-5; P22607: FGFR3; NbExp=3; IntAct=EBI-21251460, EBI-348399; CC O60260-5; Q9H2C0: GAN; NbExp=3; IntAct=EBI-21251460, EBI-764342; CC O60260-5; Q9NXC2: GFOD1; NbExp=3; IntAct=EBI-21251460, EBI-8799578; CC O60260-5; Q96IK5: GMCL1; NbExp=3; IntAct=EBI-21251460, EBI-2548508; CC O60260-5; P62879: GNB2; NbExp=3; IntAct=EBI-21251460, EBI-356942; CC O60260-5; Q7Z602: GPR141; NbExp=3; IntAct=EBI-21251460, EBI-21649723; CC O60260-5; P06396: GSN; NbExp=3; IntAct=EBI-21251460, EBI-351506; CC O60260-5; P68431: H3C12; NbExp=3; IntAct=EBI-21251460, EBI-79722; CC O60260-5; Q86YM7: HOMER1; NbExp=6; IntAct=EBI-21251460, EBI-746815; CC O60260-5; P0DMV8: HSPA1A; NbExp=6; IntAct=EBI-21251460, EBI-11052499; CC O60260-5; P11142: HSPA8; NbExp=9; IntAct=EBI-21251460, EBI-351896; CC O60260-5; Q6DN90-2: IQSEC1; NbExp=6; IntAct=EBI-21251460, EBI-21911304; CC O60260-5; Q8NA54: IQUB; NbExp=3; IntAct=EBI-21251460, EBI-10220600; CC O60260-5; P05161: ISG15; NbExp=3; IntAct=EBI-21251460, EBI-746466; CC O60260-5; Q9UKP3-2: ITGB1BP2; NbExp=3; IntAct=EBI-21251460, EBI-25856470; CC O60260-5; Q9NVX7-2: KBTBD4; NbExp=3; IntAct=EBI-21251460, EBI-25871195; CC O60260-5; Q9UIH9: KLF15; NbExp=3; IntAct=EBI-21251460, EBI-2796400; CC O60260-5; Q6TDP4: KLHL17; NbExp=3; IntAct=EBI-21251460, EBI-21328926; CC O60260-5; O94889: KLHL18; NbExp=3; IntAct=EBI-21251460, EBI-2510096; CC O60260-5; Q9Y2M5: KLHL20; NbExp=3; IntAct=EBI-21251460, EBI-714379; CC O60260-5; Q8WZ60: KLHL6; NbExp=3; IntAct=EBI-21251460, EBI-6426464; CC O60260-5; Q3SY46: KRTAP13-3; NbExp=3; IntAct=EBI-21251460, EBI-10241252; CC O60260-5; Q9BYQ4: KRTAP9-2; NbExp=3; IntAct=EBI-21251460, EBI-1044640; CC O60260-5; Q9BYZ2: LDHAL6B; NbExp=6; IntAct=EBI-21251460, EBI-1108377; CC O60260-5; Q8TBB1: LNX1; NbExp=3; IntAct=EBI-21251460, EBI-739832; CC O60260-5; O95777: LSM8; NbExp=6; IntAct=EBI-21251460, EBI-347779; CC O60260-5; Q9GZQ8: MAP1LC3B; NbExp=3; IntAct=EBI-21251460, EBI-373144; CC O60260-5; P10636-6: MAPT; NbExp=3; IntAct=EBI-21251460, EBI-7796455; CC O60260-5; P61244-4: MAX; NbExp=3; IntAct=EBI-21251460, EBI-25848049; CC O60260-5; Q8TDB4: MGARP; NbExp=6; IntAct=EBI-21251460, EBI-4397720; CC O60260-5; A4FUJ8: MKL1; NbExp=6; IntAct=EBI-21251460, EBI-21250407; CC O60260-5; P51948: MNAT1; NbExp=3; IntAct=EBI-21251460, EBI-716139; CC O60260-5; Q8N594: MPND; NbExp=3; IntAct=EBI-21251460, EBI-2512452; CC O60260-5; Q9Y483-4: MTF2; NbExp=3; IntAct=EBI-21251460, EBI-10698053; CC O60260-5; Q9NPC7: MYNN; NbExp=3; IntAct=EBI-21251460, EBI-3446748; CC O60260-5; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-21251460, EBI-1058491; CC O60260-5; Q6GQQ9-2: OTUD7B; NbExp=3; IntAct=EBI-21251460, EBI-25830200; CC O60260-5; P68402: PAFAH1B2; NbExp=3; IntAct=EBI-21251460, EBI-713724; CC O60260-5; Q9NR21-5: PARP11; NbExp=3; IntAct=EBI-21251460, EBI-17159452; CC O60260-5; Q9HBE1-4: PATZ1; NbExp=3; IntAct=EBI-21251460, EBI-11022007; CC O60260-5; Q96MG8: PCMTD1; NbExp=3; IntAct=EBI-21251460, EBI-2561395; CC O60260-5; Q9NV79: PCMTD2; NbExp=3; IntAct=EBI-21251460, EBI-6309018; CC O60260-5; Q13113: PDZK1IP1; NbExp=6; IntAct=EBI-21251460, EBI-716063; CC O60260-5; Q96LB9: PGLYRP3; NbExp=3; IntAct=EBI-21251460, EBI-12339509; CC O60260-5; Q6ZR37: PLEKHG7; NbExp=6; IntAct=EBI-21251460, EBI-12891828; CC O60260-5; P25786: PSMA1; NbExp=6; IntAct=EBI-21251460, EBI-359352; CC O60260-5; P40306: PSMB10; NbExp=3; IntAct=EBI-21251460, EBI-603329; CC O60260-5; P28070: PSMB4; NbExp=3; IntAct=EBI-21251460, EBI-603350; CC O60260-5; O60671: RAD1; NbExp=6; IntAct=EBI-21251460, EBI-721835; CC O60260-5; Q8NDN9-2: RCBTB1; NbExp=3; IntAct=EBI-21251460, EBI-25880533; CC O60260-5; P41220: RGS2; NbExp=6; IntAct=EBI-21251460, EBI-712388; CC O60260-5; A0A087WUY2: RGS3; NbExp=6; IntAct=EBI-21251460, EBI-25879714; CC O60260-5; O94844: RHOBTB1; NbExp=3; IntAct=EBI-21251460, EBI-6426999; CC O60260-5; Q8N5U6: RNF10; NbExp=3; IntAct=EBI-21251460, EBI-714023; CC O60260-5; Q9Y3C5: RNF11; NbExp=3; IntAct=EBI-21251460, EBI-396669; CC O60260-5; Q6ZNA4-2: RNF111; NbExp=6; IntAct=EBI-21251460, EBI-21535400; CC O60260-5; Q9ULX5: RNF112; NbExp=6; IntAct=EBI-21251460, EBI-25829984; CC O60260-5; Q8WVD3: RNF138; NbExp=3; IntAct=EBI-21251460, EBI-749039; CC O60260-5; Q9UBS8: RNF14; NbExp=3; IntAct=EBI-21251460, EBI-2130308; CC O60260-5; Q96A37: RNF166; NbExp=3; IntAct=EBI-21251460, EBI-2130320; CC O60260-5; Q96D59: RNF183; NbExp=3; IntAct=EBI-21251460, EBI-743938; CC O60260-5; Q96BH1: RNF25; NbExp=3; IntAct=EBI-21251460, EBI-2129220; CC O60260-5; P08865: RPSA; NbExp=3; IntAct=EBI-21251460, EBI-354112; CC O60260-5; Q8N488: RYBP; NbExp=6; IntAct=EBI-21251460, EBI-752324; CC O60260-5; Q15393: SF3B3; NbExp=3; IntAct=EBI-21251460, EBI-346977; CC O60260-5; Q2NKQ1-4: SGSM1; NbExp=6; IntAct=EBI-21251460, EBI-10182463; CC O60260-5; Q14190-2: SIM2; NbExp=3; IntAct=EBI-21251460, EBI-21623725; CC O60260-5; Q9GZS3: SKIC8; NbExp=6; IntAct=EBI-21251460, EBI-358545; CC O60260-5; Q9HCE7-2: SMURF1; NbExp=3; IntAct=EBI-21251460, EBI-9845742; CC O60260-5; P37840: SNCA; NbExp=8; IntAct=EBI-21251460, EBI-985879; CC O60260-5; Q9Y6H5-5: SNCAIP; NbExp=6; IntAct=EBI-21251460, EBI-25880040; CC O60260-5; Q96DI7: SNRNP40; NbExp=3; IntAct=EBI-21251460, EBI-538492; CC O60260-5; O14544: SOCS6; NbExp=3; IntAct=EBI-21251460, EBI-3929549; CC O60260-5; Q99932-2: SPAG8; NbExp=6; IntAct=EBI-21251460, EBI-11959123; CC O60260-5; Q8IUW3: SPATA2L; NbExp=3; IntAct=EBI-21251460, EBI-2510414; CC O60260-5; Q8TCT7-2: SPPL2B; NbExp=3; IntAct=EBI-21251460, EBI-8345366; CC O60260-5; Q7Z699: SPRED1; NbExp=3; IntAct=EBI-21251460, EBI-5235340; CC O60260-5; Q9C004: SPRY4; NbExp=3; IntAct=EBI-21251460, EBI-354861; CC O60260-5; Q96BD6: SPSB1; NbExp=3; IntAct=EBI-21251460, EBI-2659201; CC O60260-5; Q99619: SPSB2; NbExp=3; IntAct=EBI-21251460, EBI-2323209; CC O60260-5; O75886: STAM2; NbExp=3; IntAct=EBI-21251460, EBI-373258; CC O60260-5; O95630: STAMBP; NbExp=3; IntAct=EBI-21251460, EBI-396676; CC O60260-5; Q9UNE7: STUB1; NbExp=6; IntAct=EBI-21251460, EBI-357085; CC O60260-5; Q9BT88: SYT11; NbExp=6; IntAct=EBI-21251460, EBI-751770; CC O60260-5; Q13148: TARDBP; NbExp=3; IntAct=EBI-21251460, EBI-372899; CC O60260-5; Q16650: TBR1; NbExp=6; IntAct=EBI-21251460, EBI-1047158; CC O60260-5; Q15554-4: TERF2; NbExp=6; IntAct=EBI-21251460, EBI-25840535; CC O60260-5; Q04724: TLE1; NbExp=3; IntAct=EBI-21251460, EBI-711424; CC O60260-5; Q71RG4-4: TMUB2; NbExp=3; IntAct=EBI-21251460, EBI-25831574; CC O60260-5; Q9H0E2: TOLLIP; NbExp=3; IntAct=EBI-21251460, EBI-74615; CC O60260-5; P19474: TRIM21; NbExp=3; IntAct=EBI-21251460, EBI-81290; CC O60260-5; Q9UPQ4-2: TRIM35; NbExp=3; IntAct=EBI-21251460, EBI-17716262; CC O60260-5; Q8NBM4-4: UBAC2; NbExp=3; IntAct=EBI-21251460, EBI-25840976; CC O60260-5; P57075-2: UBASH3A; NbExp=6; IntAct=EBI-21251460, EBI-7353612; CC O60260-5; P0CG47: UBB; NbExp=6; IntAct=EBI-21251460, EBI-413034; CC O60260-5; O15205: UBD; NbExp=3; IntAct=EBI-21251460, EBI-6657186; CC O60260-5; Q9Y385: UBE2J1; NbExp=3; IntAct=EBI-21251460, EBI-988826; CC O60260-5; P68036: UBE2L3; NbExp=3; IntAct=EBI-21251460, EBI-711173; CC O60260-5; P61081: UBE2M; NbExp=3; IntAct=EBI-21251460, EBI-1041660; CC O60260-5; Q9C0C9: UBE2O; NbExp=3; IntAct=EBI-21251460, EBI-2339946; CC O60260-5; Q13404: UBE2V1; NbExp=3; IntAct=EBI-21251460, EBI-1050671; CC O60260-5; Q04323-2: UBXN1; NbExp=3; IntAct=EBI-21251460, EBI-11530712; CC O60260-5; Q9Y3C8: UFC1; NbExp=3; IntAct=EBI-21251460, EBI-1045733; CC O60260-5; Q96RL1-2: UIMC1; NbExp=3; IntAct=EBI-21251460, EBI-17761788; CC O60260-5; O75604-3: USP2; NbExp=3; IntAct=EBI-21251460, EBI-10696113; CC O60260-5; P18206-2: VCL; NbExp=6; IntAct=EBI-21251460, EBI-11027067; CC O60260-5; P45880: VDAC2; NbExp=6; IntAct=EBI-21251460, EBI-354022; CC O60260-5; P40337-2: VHL; NbExp=3; IntAct=EBI-21251460, EBI-12157263; CC O60260-5; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-21251460, EBI-11141397; CC O60260-5; O00308: WWP2; NbExp=3; IntAct=EBI-21251460, EBI-743923; CC O60260-5; Q04917: YWHAH; NbExp=6; IntAct=EBI-21251460, EBI-306940; CC O60260-5; O43167-2: ZBTB24; NbExp=3; IntAct=EBI-21251460, EBI-25842419; CC O60260-5; Q15916: ZBTB6; NbExp=3; IntAct=EBI-21251460, EBI-7227791; CC O60260-5; Q9Y649; NbExp=3; IntAct=EBI-21251460, EBI-25900580; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:10319893, CC ECO:0000269|PubMed:16955485, ECO:0000269|PubMed:17846173, CC ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19029340, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19501131, CC ECO:0000269|PubMed:22082830, ECO:0000269|PubMed:23620051, CC ECO:0000269|PubMed:23933751, ECO:0000269|PubMed:24898855}. Nucleus CC {ECO:0000269|PubMed:16955485}. Endoplasmic reticulum CC {ECO:0000269|PubMed:19501131}. Mitochondrion CC {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19029340, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:20889974, CC ECO:0000269|PubMed:22082830, ECO:0000269|PubMed:23620051, CC ECO:0000269|PubMed:23754282, ECO:0000269|PubMed:23933751, CC ECO:0000269|PubMed:24898855}. Mitochondrion outer membrane CC {ECO:0000250|UniProtKB:Q9WVS6}. Cell projection, neuron projection CC {ECO:0000269|PubMed:12925569}. Postsynaptic density CC {ECO:0000250|UniProtKB:Q9WVS6}. Presynapse CC {ECO:0000250|UniProtKB:Q9WVS6}. Note=Mainly localizes in the cytosol CC (PubMed:19029340, PubMed:19229105). Co-localizes with SYT11 in CC neutrites (PubMed:12925569). Co-localizes with SNCAIP in brainstem Lewy CC bodies (PubMed:10319893, PubMed:11431533). Translocates to CC dysfunctional mitochondria that have lost the mitochondrial membrane CC potential; recruitment to mitochondria is PINK1-dependent CC (PubMed:18957282, PubMed:19966284, PubMed:23620051, PubMed:24898855). CC Mitochondrial localization also gradually increases with cellular CC growth (PubMed:22082830). {ECO:0000269|PubMed:10319893, CC ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:12925569, CC ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19029340, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19966284, CC ECO:0000269|PubMed:22082830, ECO:0000269|PubMed:23620051, CC ECO:0000269|PubMed:24898855}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=8; CC Name=1; CC IsoId=O60260-1; Sequence=Displayed; CC Name=2; Synonyms=SV5DEL; CC IsoId=O60260-2; Sequence=VSP_011707; CC Name=3; CC IsoId=O60260-3; Sequence=VSP_011706, VSP_011709, VSP_011710; CC Name=4; CC IsoId=O60260-4; Sequence=VSP_011705; CC Name=5; CC IsoId=O60260-5; Sequence=VSP_011708, VSP_011711, VSP_011712; CC Name=6; CC IsoId=O60260-6; Sequence=VSP_041563; CC Name=7; Synonyms=SV5,9DEL; CC IsoId=O60260-7; Sequence=VSP_011707, VSP_053651; CC Name=8; Synonyms=SV9DEL; CC IsoId=O60260-8; Sequence=VSP_053651; CC -!- TISSUE SPECIFICITY: Highly expressed in the brain including the CC substantia nigra (PubMed:19501131, PubMed:9560156). Expressed in heart, CC testis and skeletal muscle (PubMed:9560156). Expression is down- CC regulated or absent in tumor biopsies, and absent in the brain of PARK2 CC patients (PubMed:12719539, PubMed:14614460). Overexpression protects CC dopamine neurons from kainate-mediated apoptosis (PubMed:12628165). CC Found in serum (at protein level) (PubMed:19501131). CC {ECO:0000269|PubMed:12628165, ECO:0000269|PubMed:12719539, CC ECO:0000269|PubMed:14614460, ECO:0000269|PubMed:19501131, CC ECO:0000269|PubMed:9560156}. CC -!- DOMAIN: The ubiquitin-like domain binds the PSMD4 subunit of 26S CC proteasomes. {ECO:0000269|PubMed:19801972}. CC -!- DOMAIN: The RING-type 1 zinc finger domain is required to repress CC p53/TP53 transcription. {ECO:0000269|PubMed:19801972}. CC -!- DOMAIN: Members of the RBR family are atypical E3 ligases. They CC interact with the E2 conjugating enzyme UBE2L3 and function like HECT- CC type E3 enzymes: they bind E2s via the first RING domain, but require CC an obligate trans-thiolation step during the ubiquitin transfer, CC requiring a conserved cysteine residue in the second RING domain. CC {ECO:0000269|PubMed:23770917, ECO:0000305|PubMed:21532592}. CC -!- PTM: ISGylated. Conjugated to ubiquitin-like protein ISG15 upon IFN- CC beta stimulation. ISGylation positively regulates its E3 ligase CC activity. {ECO:0000269|PubMed:27534820}. CC -!- PTM: Auto-ubiquitinates in an E2-dependent manner leading to its own CC degradation (PubMed:19229105, PubMed:23770917, PubMed:25474007). Also CC polyubiquitinated by RNF41 for proteasomal degradation CC (PubMed:19229105). {ECO:0000269|PubMed:19229105, CC ECO:0000269|PubMed:23770917, ECO:0000269|PubMed:25474007}. CC -!- PTM: S-nitrosylated. The inhibition of PRKN ubiquitin E3 ligase CC activity by S-nitrosylation could contribute to the degenerative CC process in PD by impairing the ubiquitination of PRKN substrates. CC {ECO:0000269|PubMed:15105460}. CC -!- PTM: Phosphorylated (PubMed:18957282, PubMed:23754282, PubMed:24660806, CC PubMed:24784582, PubMed:25474007). Activation requires phosphorylation CC at Ser-65 by PINK1 and binding to PINK1 phosphorylated ubiquitin CC (PubMed:18957282, PubMed:23754282, PubMed:24660806, PubMed:24784582, CC PubMed:25474007). Phosphorylation at Thr-175 by PINK1 and at Thr-217 is CC important for mitochondrial localization (PubMed:18957282). CC {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:23754282, CC ECO:0000269|PubMed:24660806, ECO:0000269|PubMed:24784582, CC ECO:0000269|PubMed:25474007}. CC -!- DISEASE: Parkinson disease (PARK) [MIM:168600]: A complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability. Additional features CC are characteristic postural abnormalities, dysautonomia, dystonic CC cramps, and dementia. The pathology of Parkinson disease involves the CC loss of dopaminergic neurons in the substantia nigra and the presence CC of Lewy bodies (intraneuronal accumulations of aggregated proteins), in CC surviving neurons in various areas of the brain. The disease is CC progressive and usually manifests after the age of 50 years, although CC early-onset cases (before 50 years) are known. The majority of the CC cases are sporadic suggesting a multifactorial etiology based on CC environmental and genetic factors. However, some patients present with CC a positive family history for the disease. Familial forms of the CC disease usually begin at earlier ages and are associated with atypical CC clinical features. {ECO:0000269|PubMed:12629236, CC ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:19966284, CC ECO:0000269|PubMed:29311685}. Note=Disease susceptibility may be CC associated with variants affecting the gene represented in this entry. CC Heterozygous mutations act as susceptibility alleles for late-onset CC Parkinson disease (PubMed:12629236, PubMed:12730996). CC -!- DISEASE: Parkinson disease 2 (PARK2) [MIM:600116]: An autosomal CC recessive form of Parkinson disease, a complex neurodegenerative CC disorder characterized by bradykinesia, resting tremor, muscular CC rigidity and postural instability. PARK2 differs from classic forms of CC Parkinson disease by early DOPA-induced dyskinesia, diurnal fluctuation CC of the symptoms, sleep benefit, dystonia and hyper-reflexia. Dementia CC is absent. Pathologically, patients show loss of dopaminergic neurons CC in the substantia nigra, similar to that seen in classic Parkinson CC disease; however, Lewy bodies (intraneuronal accumulations of CC aggregated proteins) are absent. Disease onset is usually before age 40 CC years. {ECO:0000269|PubMed:10072423, ECO:0000269|PubMed:10824074, CC ECO:0000269|PubMed:10888878, ECO:0000269|PubMed:10939576, CC ECO:0000269|PubMed:11163284, ECO:0000269|PubMed:11179010, CC ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11487568, CC ECO:0000269|PubMed:11590439, ECO:0000269|PubMed:11971093, CC ECO:0000269|PubMed:12056932, ECO:0000269|PubMed:12112109, CC ECO:0000269|PubMed:12114481, ECO:0000269|PubMed:12116199, CC ECO:0000269|PubMed:12362318, ECO:0000269|PubMed:12397156, CC ECO:0000269|PubMed:12629236, ECO:0000269|PubMed:12730996, CC ECO:0000269|PubMed:12925569, ECO:0000269|PubMed:15584030, CC ECO:0000269|PubMed:17360614, ECO:0000269|PubMed:19229105, CC ECO:0000269|PubMed:19801972, ECO:0000269|PubMed:20404107, CC ECO:0000269|PubMed:20889486, ECO:0000269|PubMed:20889974, CC ECO:0000269|PubMed:21376232, ECO:0000269|PubMed:22396657, CC ECO:0000269|PubMed:22956510, ECO:0000269|PubMed:23770917, CC ECO:0000269|PubMed:32047033, ECO:0000269|PubMed:9560156, CC ECO:0000269|PubMed:9731209}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Note=Defects in PRKN may be involved in the development and/or CC progression of ovarian cancer. CC -!- MISCELLANEOUS: The parkin locus (PRKN), adjacent to the 6q telomere is CC hyper-recombinable and lies within FRA6E, the third most common fragile CC site in tumor tissue. CC -!- SIMILARITY: Belongs to the RBR family. Parkin subfamily. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Life's tremors - Issue 131 CC of September 2011; CC URL="https://www.proteinspotlight.org/back_issues/131"; 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; AB009973; BAA25751.1; -; mRNA. DR EMBL; EF375726; ABN46990.1; -; mRNA. DR EMBL; AF381282; AAM21457.1; -; mRNA. DR EMBL; AF381283; AAM21458.1; -; mRNA. DR EMBL; AF381286; AAM21461.1; -; mRNA. DR EMBL; GU345839; ADB90270.1; -; mRNA. DR EMBL; GU345840; ADB90271.1; -; mRNA. DR EMBL; GU361467; ADB91979.1; -; mRNA. DR EMBL; AK292590; BAF85279.1; -; mRNA. DR EMBL; AL035697; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL132982; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL445215; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP000886; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP000887; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP001576; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP001577; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP001578; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP003699; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471051; EAW47573.1; -; Genomic_DNA. DR EMBL; CH471051; EAW47574.1; -; Genomic_DNA. DR EMBL; BC022014; AAH22014.1; -; mRNA. DR EMBL; AY564225; AAS88422.1; -; Genomic_DNA. DR CCDS; CCDS5281.1; -. [O60260-1] DR CCDS; CCDS5282.1; -. [O60260-2] DR CCDS; CCDS5283.1; -. [O60260-6] DR RefSeq; NP_004553.2; NM_004562.3. [O60260-1] DR RefSeq; NP_054642.2; NM_013987.3. [O60260-2] DR RefSeq; NP_054643.2; NM_013988.3. [O60260-6] DR PDB; 1IYF; NMR; -; A=1-76. DR PDB; 2JMO; NMR; -; A=308-384. DR PDB; 4BM9; X-ray; 2.25 A; A=137-465. DR PDB; 4I1F; X-ray; 1.58 A; A=141-465. DR PDB; 4I1H; X-ray; 2.00 A; A=141-465. DR PDB; 5C1Z; X-ray; 1.79 A; A/B=1-465. DR PDB; 5C23; X-ray; 2.37 A; A/B=1-465. DR PDB; 5C9V; X-ray; 2.35 A; A=137-465. DR PDB; 5N2W; X-ray; 2.68 A; A=1-465. DR PDB; 5N38; X-ray; 2.60 A; A=1-465. DR PDB; 5TR5; NMR; -; A=1-76. DR PDB; 6GLC; X-ray; 1.80 A; A=1-382. DR PDB; 6HUE; X-ray; 2.85 A; A/B=1-465. DR PDB; 6N13; NMR; -; B=144-465. DR PDB; 8IK6; X-ray; 3.30 A; A/C=139-465. DR PDB; 8IKM; X-ray; 1.92 A; A=141-382, C=1-140. DR PDB; 8IKT; X-ray; 2.60 A; A=77-382, C=1-76. DR PDB; 8IKV; X-ray; 2.35 A; A/C=139-465. DR PDB; 8JWV; X-ray; 2.90 A; A=141-465. DR PDB; 8WZN; X-ray; 1.80 A; A=141-465. DR PDB; 8WZO; X-ray; 2.25 A; A=141-465. DR PDBsum; 1IYF; -. DR PDBsum; 2JMO; -. DR PDBsum; 4BM9; -. DR PDBsum; 4I1F; -. DR PDBsum; 4I1H; -. DR PDBsum; 5C1Z; -. DR PDBsum; 5C23; -. DR PDBsum; 5C9V; -. DR PDBsum; 5N2W; -. DR PDBsum; 5N38; -. DR PDBsum; 5TR5; -. DR PDBsum; 6GLC; -. DR PDBsum; 6HUE; -. DR PDBsum; 6N13; -. DR PDBsum; 8IK6; -. DR PDBsum; 8IKM; -. DR PDBsum; 8IKT; -. DR PDBsum; 8IKV; -. DR PDBsum; 8JWV; -. DR PDBsum; 8WZN; -. DR PDBsum; 8WZO; -. DR AlphaFoldDB; O60260; -. DR BMRB; O60260; -. DR SMR; O60260; -. DR BioGRID; 111105; 3437. DR CORUM; O60260; -. DR DIP; DIP-37655N; -. DR FunCoup; O60260; 952. DR IntAct; O60260; 311. DR MINT; O60260; -. DR STRING; 9606.ENSP00000355865; -. DR BindingDB; O60260; -. DR TCDB; 8.A.52.2.1; the ubiquitin-related protein degradation (upd) family. DR GlyGen; O60260; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; O60260; -. DR PhosphoSitePlus; O60260; -. DR BioMuta; PRKN; -. DR MassIVE; O60260; -. DR PaxDb; 9606-ENSP00000355865; -. DR PeptideAtlas; O60260; -. DR ProteomicsDB; 49290; -. [O60260-1] DR ProteomicsDB; 49291; -. [O60260-2] DR ProteomicsDB; 49292; -. [O60260-3] DR ProteomicsDB; 49293; -. [O60260-4] DR ProteomicsDB; 49294; -. [O60260-5] DR ProteomicsDB; 49295; -. [O60260-6] DR Antibodypedia; 4264; 797 antibodies from 52 providers. DR DNASU; 5071; -. DR Ensembl; ENST00000366896.5; ENSP00000355862.1; ENSG00000185345.25. [O60260-6] DR Ensembl; ENST00000366897.5; ENSP00000355863.1; ENSG00000185345.25. [O60260-2] DR Ensembl; ENST00000366898.6; ENSP00000355865.1; ENSG00000185345.25. [O60260-1] DR Ensembl; ENST00000479615.5; ENSP00000434414.1; ENSG00000185345.25. [O60260-3] DR GeneID; 5071; -. DR KEGG; hsa:5071; -. DR MANE-Select; ENST00000366898.6; ENSP00000355865.1; NM_004562.3; NP_004553.2. DR UCSC; uc003qty.5; human. [O60260-1] DR AGR; HGNC:8607; -. DR CIViC; 5071; 2 evidence items across 2 molecular profiles. DR ClinPGx; PA32942; -. DR CTD; 5071; -. DR DisGeNET; 5071; -. DR GeneCards; PRKN; -. DR GeneReviews; PRKN; -. DR HGNC; HGNC:8607; PRKN. DR HPA; ENSG00000185345; Tissue enhanced (skeletal muscle, tongue). DR MalaCards; PRKN; -. DR MIM; 168600; phenotype. DR MIM; 600116; phenotype. DR MIM; 602544; gene. DR OpenTargets; ENSG00000185345; -. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000185345; -. DR eggNOG; KOG0006; Eukaryota. DR GeneTree; ENSGT00390000011034; -. DR HOGENOM; CLU_050804_0_0_1; -. DR InParanoid; O60260; -. DR OMA; DPKWDIK; -. DR OrthoDB; 1431934at2759; -. DR PAN-GO; O60260; 15 GO annotations based on evolutionary models. DR PhylomeDB; O60260; -. DR BRENDA; 2.3.2.27; 2681. DR BRENDA; 2.3.2.31; 2681. DR PathwayCommons; O60260; -. DR Reactome; R-HSA-5205685; PINK1-PRKN Mediated Mitophagy. DR Reactome; R-HSA-5675482; Regulation of necroptotic cell death. DR Reactome; R-HSA-5689877; Josephin domain DUBs. DR Reactome; R-HSA-9646399; Aggrephagy. DR Reactome; R-HSA-977225; Amyloid fiber formation. DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation. DR SignaLink; O60260; -. DR SIGNOR; O60260; -. DR UniPathway; UPA00143; -. DR Agora; ENSG00000185345; -. DR BioGRID-ORCS; 5071; 13 hits in 1187 CRISPR screens. DR CD-CODE; 8C2F96ED; Centrosome. DR ChiTaRS; PARK2; human. DR EvolutionaryTrace; O60260; -. DR GeneWiki; Parkin_(ligase); -. DR GenomeRNAi; 5071; -. DR Pharos; O60260; Tbio. DR PRO; PR:O60260; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; O60260; protein. DR Bgee; ENSG00000185345; Expressed in sural nerve and 107 other cell types or tissues. DR ExpressionAtlas; O60260; baseline and differential. DR GO; GO:0016235; C:aggresome; IDA:BHF-UCL. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0098691; C:dopaminergic synapse; IEA:Ensembl. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:ParkinsonsUK-UCL. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:Ensembl. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0000139; C:Golgi membrane; IEA:Ensembl. DR GO; GO:0097413; C:Lewy body; TAS:ParkinsonsUK-UCL. DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:UniProt. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0043005; C:neuron projection; IDA:ParkinsonsUK-UCL. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0016607; C:nuclear speck; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:ParkinsonsUK-UCL. DR GO; GO:1990452; C:Parkin-FBXW7-Cul1 ubiquitin ligase complex; IPI:ParkinsonsUK-UCL. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0014069; C:postsynaptic density; IEA:UniProtKB-SubCell. DR GO; GO:0030672; C:synaptic vesicle membrane; IEA:Ensembl. DR GO; GO:0043195; C:terminal bouton; IEA:Ensembl. DR GO; GO:0000151; C:ubiquitin ligase complex; IDA:UniProtKB. DR GO; GO:0003779; F:actin binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0008013; F:beta-catenin binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0097602; F:cullin family protein binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0019899; F:enzyme binding; IPI:ParkinsonsUK-UCL. DR GO; GO:1990444; F:F-box domain binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0001664; F:G protein-coupled receptor binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0031072; F:heat shock protein binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0042826; F:histone deacetylase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0030544; F:Hsp70 protein binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0019900; F:kinase binding; IPI:UniProtKB. DR GO; GO:0030165; F:PDZ domain binding; IPI:BHF-UCL. DR GO; GO:0043274; F:phospholipase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB. DR GO; GO:0044877; F:protein-containing complex binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0051087; F:protein-folding chaperone binding; IPI:BHF-UCL. DR GO; GO:0017124; F:SH3 domain binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0003714; F:transcription corepressor activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0015631; F:tubulin binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB. DR GO; GO:0031624; F:ubiquitin conjugating enzyme binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IMP:UniProtKB. DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB. DR GO; GO:1990381; F:ubiquitin-specific protease binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0008270; F:zinc ion binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0008344; P:adult locomotory behavior; ISS:ParkinsonsUK-UCL. DR GO; GO:0070842; P:aggresome assembly; IMP:BHF-UCL. DR GO; GO:1990000; P:amyloid fibril formation; TAS:Reactome. DR GO; GO:0000422; P:autophagy of mitochondrion; IDA:UniProtKB. DR GO; GO:1903351; P:cellular response to dopamine; TAS:ParkinsonsUK-UCL. DR GO; GO:1904881; P:cellular response to hydrogen sulfide; IEA:Ensembl. DR GO; GO:1905232; P:cellular response to L-glutamate; IEA:Ensembl. DR GO; GO:1904845; P:cellular response to L-glutamine; IEA:Ensembl. DR GO; GO:0071287; P:cellular response to manganese ion; TAS:ParkinsonsUK-UCL. DR GO; GO:0034599; P:cellular response to oxidative stress; TAS:ParkinsonsUK-UCL. DR GO; GO:0097237; P:cellular response to toxic substance; IMP:ParkinsonsUK-UCL. DR GO; GO:0034620; P:cellular response to unfolded protein; TAS:ParkinsonsUK-UCL. DR GO; GO:0007417; P:central nervous system development; TAS:ProtInc. DR GO; GO:0042417; P:dopamine metabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0051583; P:dopamine uptake involved in synaptic transmission; IEA:Ensembl. DR GO; GO:0036503; P:ERAD pathway; NAS:ParkinsonsUK-UCL. DR GO; GO:0010994; P:free ubiquitin chain polymerization; IMP:ParkinsonsUK-UCL. DR GO; GO:0044828; P:host-mediated suppression of viral genome replication; IDA:AgBase. DR GO; GO:0007612; P:learning; IEA:Ensembl. DR GO; GO:0016236; P:macroautophagy; TAS:Reactome. DR GO; GO:0000266; P:mitochondrial fission; ISS:ParkinsonsUK-UCL. DR GO; GO:0043653; P:mitochondrial fragmentation involved in apoptotic process; IEA:Ensembl. DR GO; GO:0051646; P:mitochondrion localization; IEA:Ensembl. DR GO; GO:0007005; P:mitochondrion organization; ISS:ParkinsonsUK-UCL. DR GO; GO:0099074; P:mitochondrion to lysosome vesicle-mediated transport; IDA:ParkinsonsUK-UCL. DR GO; GO:0000423; P:mitophagy; IDA:UniProtKB. DR GO; GO:0050804; P:modulation of chemical synaptic transmission; IBA:GO_Central. DR GO; GO:0032232; P:negative regulation of actin filament bundle assembly; IDA:BHF-UCL. DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1902236; P:negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1903382; P:negative regulation of endoplasmic reticulum stress-induced neuron intrinsic apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0090394; P:negative regulation of excitatory postsynaptic potential; IEA:Ensembl. DR GO; GO:1903542; P:negative regulation of exosomal secretion; IMP:ParkinsonsUK-UCL. DR GO; GO:0010629; P:negative regulation of gene expression; IMP:BHF-UCL. DR GO; GO:0033132; P:negative regulation of glucokinase activity; IDA:MGI. DR GO; GO:0046676; P:negative regulation of insulin secretion; IDA:MGI. DR GO; GO:1905366; P:negative regulation of intralumenal vesicle formation; IMP:ParkinsonsUK-UCL. DR GO; GO:1902254; P:negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator; IMP:ParkinsonsUK-UCL. DR GO; GO:0046329; P:negative regulation of JNK cascade; ISS:ParkinsonsUK-UCL. DR GO; GO:0090258; P:negative regulation of mitochondrial fission; IEA:Ensembl. DR GO; GO:0010637; P:negative regulation of mitochondrial fusion; ISS:ParkinsonsUK-UCL. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:ParkinsonsUK-UCL. DR GO; GO:1903377; P:negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1903427; P:negative regulation of reactive oxygen species biosynthetic process; IEA:Ensembl. DR GO; GO:2000378; P:negative regulation of reactive oxygen species metabolic process; IGI:ParkinsonsUK-UCL. DR GO; GO:0090201; P:negative regulation of release of cytochrome c from mitochondria; IDA:BHF-UCL. DR GO; GO:1904049; P:negative regulation of spontaneous neurotransmitter secretion; IMP:ParkinsonsUK-UCL. DR GO; GO:0051967; P:negative regulation of synaptic transmission, glutamatergic; IEA:Ensembl. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:ParkinsonsUK-UCL. DR GO; GO:0070050; P:neuron cellular homeostasis; ISS:ParkinsonsUK-UCL. DR GO; GO:0042415; P:norepinephrine metabolic process; IEA:Ensembl. DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl. DR GO; GO:2001171; P:positive regulation of ATP biosynthetic process; IEA:Ensembl. DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IDA:ParkinsonsUK-UCL. DR GO; GO:1903861; P:positive regulation of dendrite extension; IEA:Ensembl. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:ParkinsonsUK-UCL. DR GO; GO:0035774; P:positive regulation of insulin secretion involved in cellular response to glucose stimulus; IEA:Ensembl. DR GO; GO:0090141; P:positive regulation of mitochondrial fission; ISS:ParkinsonsUK-UCL. DR GO; GO:0010636; P:positive regulation of mitochondrial fusion; IMP:ParkinsonsUK-UCL. DR GO; GO:0010918; P:positive regulation of mitochondrial membrane potential; IEA:Ensembl. DR GO; GO:1901526; P:positive regulation of mitophagy; IDA:ParkinsonsUK-UCL. DR GO; GO:0051582; P:positive regulation of neurotransmitter uptake; IMP:ParkinsonsUK-UCL. DR GO; GO:1901800; P:positive regulation of proteasomal protein catabolic process; IGI:ParkinsonsUK-UCL. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0045732; P:positive regulation of protein catabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:1902530; P:positive regulation of protein linear polyubiquitination; IGI:ParkinsonsUK-UCL. DR GO; GO:1905477; P:positive regulation of protein localization to membrane; IMP:ParkinsonsUK-UCL. DR GO; GO:1905281; P:positive regulation of retrograde transport, endosome to Golgi; NAS:ParkinsonsUK-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:ParkinsonsUK-UCL. DR GO; GO:1903265; P:positive regulation of tumor necrosis factor-mediated signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1905091; P:positive regulation of type 2 mitophagy; IDA:ParkinsonsUK-UCL. DR GO; GO:0010498; P:proteasomal protein catabolic process; IMP:BHF-UCL. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0051865; P:protein autoubiquitination; IDA:UniProtKB. DR GO; GO:0031648; P:protein destabilization; IDA:UniProtKB. DR GO; GO:0016579; P:protein deubiquitination; TAS:Reactome. DR GO; GO:0070979; P:protein K11-linked ubiquitination; IDA:UniProtKB. DR GO; GO:0044314; P:protein K27-linked ubiquitination; IDA:UniProt. DR GO; GO:0035519; P:protein K29-linked ubiquitination; TAS:ParkinsonsUK-UCL. DR GO; GO:0070936; P:protein K48-linked ubiquitination; IDA:ParkinsonsUK-UCL. DR GO; GO:0085020; P:protein K6-linked ubiquitination; IDA:UniProtKB. DR GO; GO:0070534; P:protein K63-linked ubiquitination; IDA:UniProtKB. DR GO; GO:0070585; P:protein localization to mitochondrion; IEA:Ensembl. DR GO; GO:0006513; P:protein monoubiquitination; IDA:UniProtKB. DR GO; GO:0000209; P:protein polyubiquitination; IDA:UniProtKB. DR GO; GO:0050821; P:protein stabilization; IMP:UniProtKB. DR GO; GO:0016567; P:protein ubiquitination; IDA:ParkinsonsUK-UCL. DR GO; GO:0042981; P:regulation of apoptotic process; IBA:GO_Central. DR GO; GO:0010506; P:regulation of autophagy; IDA:UniProtKB. DR GO; GO:0060828; P:regulation of canonical Wnt signaling pathway; TAS:ParkinsonsUK-UCL. DR GO; GO:1900407; P:regulation of cellular response to oxidative stress; IDA:ParkinsonsUK-UCL. DR GO; GO:0042053; P:regulation of dopamine metabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:0014059; P:regulation of dopamine secretion; TAS:ParkinsonsUK-UCL. DR GO; GO:0010906; P:regulation of glucose metabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0032368; P:regulation of lipid transport; TAS:ParkinsonsUK-UCL. DR GO; GO:0010821; P:regulation of mitochondrion organization; IDA:ParkinsonsUK-UCL. DR GO; GO:0060544; P:regulation of necroptotic process; TAS:Reactome. DR GO; GO:0099072; P:regulation of postsynaptic membrane neurotransmitter receptor levels; IEA:Ensembl. DR GO; GO:0031647; P:regulation of protein stability; IMP:ParkinsonsUK-UCL. DR GO; GO:1903214; P:regulation of protein targeting to mitochondrion; NAS:ParkinsonsUK-UCL. DR GO; GO:0031396; P:regulation of protein ubiquitination; IMP:ParkinsonsUK-UCL. DR GO; GO:2000377; P:regulation of reactive oxygen species metabolic process; IMP:UniProtKB. DR GO; GO:1900242; P:regulation of synaptic vesicle endocytosis; IEA:Ensembl. DR GO; GO:1902803; P:regulation of synaptic vesicle transport; NAS:ParkinsonsUK-UCL. DR GO; GO:0140251; P:regulation protein catabolic process at presynapse; IEA:Ensembl. DR GO; GO:0051412; P:response to corticosterone; IEA:Ensembl. DR GO; GO:1904643; P:response to curcumin; IEA:Ensembl. DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IMP:ParkinsonsUK-UCL. DR GO; GO:0014850; P:response to muscle activity; IEA:Ensembl. DR GO; GO:0006979; P:response to oxidative stress; ISS:ParkinsonsUK-UCL. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0001964; P:startle response; IEA:Ensembl. DR GO; GO:0035249; P:synaptic transmission, glutamatergic; IEA:Ensembl. DR GO; GO:0061734; P:type 2 mitophagy; IDA:ParkinsonsUK-UCL. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:UniProtKB. DR CDD; cd20340; BRcat_RBR_parkin; 1. DR CDD; cd20357; Rcat_RBR_parkin; 1. DR CDD; cd16627; RING-HC_RBR_parkin; 1. DR CDD; cd21382; RING0_parkin; 1. DR CDD; cd01798; Ubl_parkin; 1. DR DisProt; DP01849; -. DR FunFam; 1.20.120.1750:FF:000009; E3 ubiquitin-protein ligase parkin; 1. DR FunFam; 2.20.25.20:FF:000008; E3 ubiquitin-protein ligase parkin; 1. DR FunFam; 3.10.20.90:FF:000142; E3 ubiquitin-protein ligase parkin; 1. DR Gene3D; 1.20.120.1750; -; 1. DR Gene3D; 2.20.25.20; -; 1. DR Gene3D; 3.10.20.90; Phosphatidylinositol 3-kinase Catalytic Subunit, Chain A, domain 1; 1. DR IDEAL; IID00008; -. DR InterPro; IPR047534; BRcat_RBR_parkin. DR InterPro; IPR002867; IBR_dom. DR InterPro; IPR003977; Parkin. DR InterPro; IPR054694; Parkin-like_IBR. DR InterPro; IPR041565; Parkin_Znf-RING. DR InterPro; IPR047536; Rcat_RBR_parkin. DR InterPro; IPR047535; RING-HC_RBR_parkin. DR InterPro; IPR044066; TRIAD_supradom. DR InterPro; IPR015496; Ubiquilin. DR InterPro; IPR000626; Ubiquitin-like_dom. DR InterPro; IPR029071; Ubiquitin-like_domsf. DR InterPro; IPR041170; Znf-RING_14. DR PANTHER; PTHR10677; UBIQUILIN; 1. DR PANTHER; PTHR10677:SF40; UBIQUITIN-LIKE DOMAIN-CONTAINING PROTEIN; 1. DR Pfam; PF22605; IBR_2; 1. DR Pfam; PF00240; ubiquitin; 1. DR Pfam; PF17976; zf-RING_12; 1. DR Pfam; PF17978; zf-RING_14; 1. DR PIRSF; PIRSF037880; Parkin; 1. DR PRINTS; PR01475; PARKIN. DR SMART; SM00647; IBR; 2. DR SMART; SM00213; UBQ; 1. DR SUPFAM; SSF57850; RING/U-box; 1. DR SUPFAM; SSF54236; Ubiquitin-like; 1. DR PROSITE; PS51873; TRIAD; 1. DR PROSITE; PS50053; UBIQUITIN_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Autophagy; Cell projection; Cytoplasm; KW Disease variant; Endoplasmic reticulum; Isopeptide bond; Membrane; KW Metal-binding; Mitochondrion; Mitochondrion outer membrane; KW Neurodegeneration; Nucleus; Parkinson disease; Parkinsonism; KW Phosphoprotein; Proteomics identification; Reference proteome; Repeat; KW S-nitrosylation; Synapse; Transcription; Transcription regulation; KW Transferase; Ubl conjugation; Ubl conjugation pathway; Zinc; Zinc-finger. FT CHAIN 1..465 FT /note="E3 ubiquitin-protein ligase parkin" FT /id="PRO_0000058576" FT DOMAIN 1..76 FT /note="Ubiquitin-like" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00214" FT ZN_FING 141..225 FT /note="RING-type 0; atypical" FT ZN_FING 238..293 FT /note="RING-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT ZN_FING 313..377 FT /note="IBR-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT ZN_FING 418..449 FT /note="RING-type 2; atypical" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT REGION 77..237 FT /note="Necessary for PINK1-dependent localization to FT mitochondria" FT /evidence="ECO:0000269|PubMed:18957282" FT REGION 77..99 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 204..238 FT /note="SYT11 binding 1" FT /evidence="ECO:0000269|PubMed:12925569" FT REGION 234..465 FT /note="TRIAD supradomain" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT REGION 257..293 FT /note="SYT11 binding 2" FT /evidence="ECO:0000269|PubMed:12925569" FT REGION 378..410 FT /note="REP" FT /evidence="ECO:0000250|UniProtKB:Q9JK66" FT ACT_SITE 431 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 238 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 241 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 253 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 257 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 260 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 263 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 289 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 293 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 332 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 337 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 352 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 360 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 365 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 368 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 373 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 377 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 418 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 421 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 436 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 441 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 446 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 449 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 457 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 461 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT MOD_RES 65 FT /note="Phosphoserine; by PINK1" FT /evidence="ECO:0000269|PubMed:18957282, FT ECO:0000269|PubMed:23754282, ECO:0000269|PubMed:24660806, FT ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:25474007" FT MOD_RES 175 FT /note="Phosphothreonine; by PINK1" FT /evidence="ECO:0000269|PubMed:18957282" FT MOD_RES 217 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:18957282" FT CROSSLNK 349 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ISG15)" FT /evidence="ECO:0000269|PubMed:27534820" FT CROSSLNK 369 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ISG15)" FT /evidence="ECO:0000269|PubMed:27534820" FT VAR_SEQ 1..191 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_011705" FT VAR_SEQ 1..79 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_011706" FT VAR_SEQ 58..206 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000305" FT /id="VSP_041563" FT VAR_SEQ 179..206 FT /note="Missing (in isoform 2 and isoform 7)" FT /evidence="ECO:0000303|PubMed:9560156, ECO:0000303|Ref.4" FT /id="VSP_011707" FT VAR_SEQ 290 FT /note="V -> VGTGDTVVLRGALGGFRRGV (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_011708" FT VAR_SEQ 291..297 FT /note="AGCPNSL -> VCLLPGM (in isoform 3)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_011709" FT VAR_SEQ 298..465 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_011710" FT VAR_SEQ 312..361 FT /note="Missing (in isoform 7 and isoform 8)" FT /evidence="ECO:0000303|Ref.4" FT /id="VSP_053651" FT VAR_SEQ 362..368 FT /note="FAFCREC -> YGQRRTK (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_011711" FT VAR_SEQ 369..465 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_011712" FT VARIANT 15 FT /note="V -> M (in PARK2; dbSNP:rs532703934)" FT /evidence="ECO:0000269|PubMed:12397156" FT /id="VAR_019733" FT VARIANT 33 FT /note="R -> Q (in PARK2; dbSNP:rs147757966)" FT /evidence="ECO:0000269|PubMed:12730996" FT /id="VAR_019734" FT VARIANT 37 FT /note="P -> L (in PARK2; dbSNP:rs148990138)" FT /evidence="ECO:0000269|PubMed:12112109" FT /id="VAR_019735" FT VARIANT 42 FT /note="R -> P (in PARK2 and PARK; induces a conformational FT change in the PSMD4-binding site of Ubl resulting in FT impaired proteasomal binding; decreases ubiquitination and FT degradation; increased aggregation; impairs the ability to FT ubiquitinate and degrade SYT11; dbSNP:rs368134308)" FT /evidence="ECO:0000269|PubMed:10888878, FT ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11971093, FT ECO:0000269|PubMed:15584030, ECO:0000269|PubMed:19229105, FT ECO:0000269|PubMed:20889486, ECO:0000269|PubMed:29311685" FT /id="VAR_019736" FT VARIANT 46 FT /note="A -> P (in PARK2)" FT /evidence="ECO:0000269|PubMed:12362318" FT /id="VAR_019737" FT VARIANT 56 FT /note="V -> E (in PARK2; dbSNP:rs137853059)" FT /evidence="ECO:0000269|PubMed:12056932" FT /id="VAR_070078" FT VARIANT 82 FT /note="A -> E (in PARK2; dbSNP:rs55774500)" FT /evidence="ECO:0000269|PubMed:11487568, FT ECO:0000269|PubMed:12116199, ECO:0000269|PubMed:12730996" FT /id="VAR_019738" FT VARIANT 92 FT /note="A -> V (in PARK2; dbSNP:rs566229879)" FT /id="VAR_019739" FT VARIANT 100 FT /note="Q -> H (in dbSNP:rs1256316516)" FT /evidence="ECO:0000269|PubMed:12781599" FT /id="VAR_019740" FT VARIANT 161 FT /note="K -> N (in PARK2; severely compromises the FT mitochondrial localization; fails to stabilize BCL2; FT decreased binding to the TP53 promoter; abolishes TP53 FT transcriptional repression; dbSNP:rs137853057)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10824074, ECO:0000269|PubMed:19801972, FT ECO:0000269|PubMed:20404107, ECO:0000269|PubMed:20889974" FT /id="VAR_019741" FT VARIANT 167 FT /note="S -> N (in dbSNP:rs1801474)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10511432, ECO:0000269|PubMed:10965160, FT ECO:0000269|PubMed:12629236" FT /id="VAR_019742" FT VARIANT 192 FT /note="M -> L (in PARK2; uncertain significance; FT dbSNP:rs9456735)" FT /evidence="ECO:0000269|PubMed:11971093" FT /id="VAR_054107" FT VARIANT 192 FT /note="M -> V (in PARK2; uncertain significance; FT dbSNP:rs9456735)" FT /evidence="ECO:0000269|PubMed:12629236" FT /id="VAR_019743" FT VARIANT 211 FT /note="K -> N (in PARK2; severely compromises the FT mitochondrial localization; fails to stabilize BCL2; loss FT of activity towards MIRO1; dbSNP:rs137853060)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:11179010, ECO:0000269|PubMed:12114481, FT ECO:0000269|PubMed:12629236, ECO:0000269|PubMed:20404107, FT ECO:0000269|PubMed:22396657" FT /id="VAR_019744" FT VARIANT 212 FT /note="C -> Y (in PARK2; dbSNP:rs137853058)" FT /evidence="ECO:0000269|PubMed:11163284, FT ECO:0000269|PubMed:12056932" FT /id="VAR_019746" FT VARIANT 240 FT /note="T -> M (in PARK2; dbSNP:rs137853054)" FT /evidence="ECO:0000269|PubMed:12629236" FT /id="VAR_019747" FT VARIANT 240 FT /note="T -> R (in PARK2; impairs the ability to FT ubiquitinate SNCAIP and BCL2; loss of UBE2L3 binding; FT severely compromises the mitochondrial localization; FT dbSNP:rs137853054)" FT /evidence="ECO:0000269|PubMed:10888878, FT ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11590439, FT ECO:0000269|PubMed:20404107, ECO:0000269|PubMed:20889974, FT ECO:0000269|PubMed:9731209" FT /id="VAR_019748" FT VARIANT 253 FT /note="C -> Y (in PARK; late onset; dbSNP:rs747427602)" FT /evidence="ECO:0000269|PubMed:12730996" FT /id="VAR_019749" FT VARIANT 256 FT /note="R -> C (in PARK2 and PARK; uncertain significance; FT impairs the ability to ubiquitinate SNCAIP and ZNF746; FT decreased binding to the TP53 promoter; abolishes TP53 FT transcriptional repression; dbSNP:rs150562946)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10824074, ECO:0000269|PubMed:11590439, FT ECO:0000269|PubMed:11971093, ECO:0000269|PubMed:12116199, FT ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:19801972" FT /id="VAR_019750" FT VARIANT 271 FT /note="R -> S (in dbSNP:rs772622421)" FT /evidence="ECO:0000269|PubMed:12781599" FT /id="VAR_019751" FT VARIANT 275 FT /note="R -> W (in PARK2 and PARK; impairs the ability to FT ubiquitinate SNCAIP; abolishes p53/TP53 transcriptional FT repression; impairs the ability to ubiquitinate and degrade FT SYT11; dbSNP:rs34424986)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10824074, ECO:0000269|PubMed:11179010, FT ECO:0000269|PubMed:11590439, ECO:0000269|PubMed:11971093, FT ECO:0000269|PubMed:12114481, ECO:0000269|PubMed:12116199, FT ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:19801972, FT ECO:0000269|PubMed:21376232, ECO:0000269|PubMed:22956510, FT ECO:0000269|PubMed:29311685" FT /id="VAR_019752" FT VARIANT 280 FT /note="D -> N (in PARK; does not affect PINK-1 dependent FT localization to depolarized mitochondria; FT dbSNP:rs72480422)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:20404107" FT /id="VAR_019753" FT VARIANT 284 FT /note="G -> R (in PARK2; dbSNP:rs751037529)" FT /id="VAR_019754" FT VARIANT 289 FT /note="C -> G (in PARK2; increased aggregation; fails to FT ubiquitinate SYT11; loses ability to bind SYT11; impaired FT relocalization to damaged mitochondria; loss of function in FT mitophagy; dbSNP:rs55961220)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:12925569, ECO:0000269|PubMed:20889486" FT /id="VAR_019755" FT VARIANT 311 FT /note="Q -> R (in a patient with Parkinson disease; FT uncertain significance)" FT /evidence="ECO:0000269|PubMed:19501131" FT /id="VAR_062672" FT VARIANT 328 FT /note="G -> E (in PARK2; does not affect PINK-1 dependent FT localization to depolarized mitochondria)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:12116199, ECO:0000269|PubMed:20404107" FT /id="VAR_019756" FT VARIANT 334 FT /note="R -> C (in dbSNP:rs199657839)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:27535533" FT /id="VAR_019757" FT VARIANT 339 FT /note="A -> S (in dbSNP:rs1554274880)" FT /evidence="ECO:0000269|PubMed:12781599" FT /id="VAR_019758" FT VARIANT 351 FT /note="T -> P (in PARK2; impairs folding of IBR domain; FT dbSNP:rs1554274861)" FT /evidence="ECO:0000269|PubMed:12112109, FT ECO:0000269|PubMed:17360614" FT /id="VAR_019759" FT VARIANT 366 FT /note="R -> W (in dbSNP:rs56092260)" FT /evidence="ECO:0000269|PubMed:10965160" FT /id="VAR_019760" FT VARIANT 371 FT /note="A -> T (in a patient with Parkinson disease; FT uncertain significance)" FT /evidence="ECO:0000269|PubMed:19501131" FT /id="VAR_062673" FT VARIANT 380 FT /note="V -> L (in dbSNP:rs1801582)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10965160, ECO:0000269|PubMed:12397156, FT ECO:0000269|PubMed:12730996" FT /id="VAR_019761" FT VARIANT 394 FT /note="D -> N (in dbSNP:rs1801334)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:12397156, ECO:0000269|PubMed:12730996" FT /id="VAR_019762" FT VARIANT 402 FT /note="R -> C (in PARK2; dbSNP:rs55830907)" FT /evidence="ECO:0000269|PubMed:15584030" FT /id="VAR_070079" FT VARIANT 415 FT /note="T -> N (in PARK2; loss of activity and self- FT ubiquitination; impairs the ability to ubiquitinate SNCAIP; FT no effect on polyubiquitination or mitophagy; does not FT affect turnover of CDCRE1; impairs PINK1-dependent FT localization to dysfunctional depolarized mitochondria; FT dbSNP:rs778125254)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10824074, ECO:0000269|PubMed:11590439, FT ECO:0000269|PubMed:15584030, ECO:0000269|PubMed:19966284, FT ECO:0000269|PubMed:22396657, ECO:0000269|PubMed:23770917, FT ECO:0000269|PubMed:32047033" FT /id="VAR_019763" FT VARIANT 418 FT /note="C -> R (in PARK2; decreased binding to the TP53 FT promoter; abolishes TP53 transcriptional repression; fails FT to ubiquitinate SYT11 but does not loose ability to bind FT SYT11; dbSNP:rs1554252200)" FT /evidence="ECO:0000269|PubMed:12925569, FT ECO:0000269|PubMed:15584030, ECO:0000269|PubMed:19801972" FT /id="VAR_070080" FT VARIANT 430 FT /note="G -> D (in PARK2; loss of self-ubiquitination; FT impairs PINK1-dependent localization to dysfunctional FT depolarized mitochondria; impaired E3 ubiquitin-protein FT ligase toward ZNF746; dbSNP:rs191486604)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:11179010, ECO:0000269|PubMed:11971093, FT ECO:0000269|PubMed:12114481, ECO:0000269|PubMed:12730996, FT ECO:0000269|PubMed:19966284, ECO:0000269|PubMed:21376232, FT ECO:0000269|PubMed:23770917" FT /id="VAR_019764" FT VARIANT 431 FT /note="C -> F (in PARK2; impaired E3 ubiquitin-protein FT ligase toward ZNF746 and BCL2; dbSNP:rs397514694)" FT /evidence="ECO:0000269|PubMed:10939576, FT ECO:0000269|PubMed:20889974, ECO:0000269|PubMed:21376232" FT /id="VAR_019765" FT VARIANT 437 FT /note="P -> L (in PARK2; impaired E3 ubiquitin-protein FT ligase toward BCL2; dbSNP:rs149953814)" FT /evidence="ECO:0000269|PubMed:11971093, FT ECO:0000269|PubMed:12114481, ECO:0000269|PubMed:12629236, FT ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:20889974" FT /id="VAR_019766" FT VARIANT 441 FT /note="C -> R (in PARK2; decreased binding to the TP53 FT promoter; abolishes TP53 transcriptional repression; FT dbSNP:rs778305273)" FT /evidence="ECO:0000269|PubMed:12116199, FT ECO:0000269|PubMed:19801972" FT /id="VAR_019767" FT MUTAGEN 65 FT /note="S->A: Loss of phosphorylation. Undergoes FT autoubiquitination in the presence of phosphorylated FT ubiquitin." FT /evidence="ECO:0000269|PubMed:25474007" FT MUTAGEN 65 FT /note="S->E: Phosphomimetic mutant; still requires PINK1 FT for activation. PRKN is activated in presence of FT phosphorylated ubiquitin." FT /evidence="ECO:0000269|PubMed:24660806, FT ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:25474007" FT MUTAGEN 175 FT /note="T->A: Loss of phosphorylation. Reduced mitochondrial FT localization; when associated with A-217." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 175 FT /note="T->E: Phosphomimetic mutant. Mostly localizes to the FT mitochondria; when associated with E-217." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 217 FT /note="T->A: Loss of phosphorylation. Reduced mitochondrial FT localization; when associated with A-175." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 217 FT /note="T->E: Phosphomimetic mutant. Mostly localizes to the FT mitochondria; when associated with E-175." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 238 FT /note="C->S: Loss of mitochondrial localization." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 332 FT /note="C->S: Impairs folding of IBR domain." FT /evidence="ECO:0000269|PubMed:17360614" FT MUTAGEN 337 FT /note="C->A: Impairs the ability to ubiquitinate SNCAIP." FT /evidence="ECO:0000269|PubMed:11590439" FT MUTAGEN 365 FT /note="C->S: Impairs protein folding." FT /evidence="ECO:0000269|PubMed:17360614" FT MUTAGEN 403 FT /note="W->A: Decreased autoinhibition and increased E3 FT activity." FT /evidence="ECO:0000269|PubMed:24784582" FT MUTAGEN 421 FT /note="C->A: Impairs the ability of self-ubiquitination and FT to ubiquitinate SNCAIP." FT /evidence="ECO:0000269|PubMed:11590439, FT ECO:0000269|PubMed:18541373" FT MUTAGEN 429 FT /note="G->E: Reduced self-ubiquitination." FT /evidence="ECO:0000269|PubMed:23770917" FT MUTAGEN 431 FT /note="C->A: Loss of activity." FT /evidence="ECO:0000269|PubMed:23770917" FT MUTAGEN 431 FT /note="C->S: Impairs the ability to ubiquitinate target FT proteins. No effect on translocation to mitochondria." FT /evidence="ECO:0000269|PubMed:11590439, FT ECO:0000269|PubMed:23727886, ECO:0000269|PubMed:23770887, FT ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:32047033" FT MUTAGEN 433 FT /note="H->N,A: Impaired activity." FT /evidence="ECO:0000269|PubMed:23727886, FT ECO:0000269|PubMed:23770887" FT MUTAGEN 444 FT /note="E->Q,A: Impaired activity." FT /evidence="ECO:0000269|PubMed:23727886, FT ECO:0000269|PubMed:23770887" FT CONFLICT 223 FT /note="S -> P (in Ref. 1; BAA25751 and 3; AAM21458/ FT AAM21457)" FT /evidence="ECO:0000305" FT CONFLICT 289..290 FT /note="CV -> MI (in Ref. 2; AAM21461)" FT /evidence="ECO:0000305" FT CONFLICT 339 FT /note="A -> V (in Ref. 9; AAS88422)" FT /evidence="ECO:0000305" FT STRAND 2..11 FT /evidence="ECO:0007829|PDB:5C1Z" FT STRAND 13..16 FT /evidence="ECO:0007829|PDB:5C1Z" FT STRAND 19..21 FT /evidence="ECO:0007829|PDB:1IYF" FT HELIX 23..34 FT /evidence="ECO:0007829|PDB:5C1Z" FT HELIX 38..40 FT /evidence="ECO:0007829|PDB:5C1Z" FT STRAND 41..45 FT /evidence="ECO:0007829|PDB:5C1Z" FT STRAND 48..50 FT /evidence="ECO:0007829|PDB:5C1Z" FT TURN 52..55 FT /evidence="ECO:0007829|PDB:1IYF" FT HELIX 56..59 FT /evidence="ECO:0007829|PDB:5C1Z" FT TURN 62..64 FT /evidence="ECO:0007829|PDB:5N2W" FT STRAND 66..71 FT /evidence="ECO:0007829|PDB:5C1Z" FT HELIX 102..104 FT /evidence="ECO:0007829|PDB:6GLC" FT STRAND 147..150 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 152..154 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 156..166 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 167..169 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 174..178 FT /evidence="ECO:0007829|PDB:4I1F" FT HELIX 183..187 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 188..190 FT /evidence="ECO:0007829|PDB:8WZO" FT STRAND 192..196 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 198..200 FT /evidence="ECO:0007829|PDB:5N38" FT STRAND 205..212 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 223..225 FT /evidence="ECO:0007829|PDB:4I1H" FT TURN 239..241 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 246..250 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 257..260 FT /evidence="ECO:0007829|PDB:4I1F" FT HELIX 261..273 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 278..280 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 281..283 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 284..286 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 290..292 FT /evidence="ECO:0007829|PDB:6N13" FT HELIX 301..307 FT /evidence="ECO:0007829|PDB:4I1F" FT HELIX 309..326 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 335..337 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 340..342 FT /evidence="ECO:0007829|PDB:6GLC" FT STRAND 348..351 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 355..358 FT /evidence="ECO:0007829|PDB:8WZN" FT STRAND 363..365 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 366..368 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 374..376 FT /evidence="ECO:0007829|PDB:6GLC" FT HELIX 379..381 FT /evidence="ECO:0007829|PDB:4BM9" FT HELIX 395..400 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 403..406 FT /evidence="ECO:0007829|PDB:8WZN" FT STRAND 414..417 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 419..421 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 424..426 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 429..431 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 433..435 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 439..441 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 444..446 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 447..449 FT /evidence="ECO:0007829|PDB:4I1F" FT HELIX 455..461 FT /evidence="ECO:0007829|PDB:4I1F" SQ SEQUENCE 465 AA; 51641 MW; 9A8BB802A3FC84C3 CRC64; MIVFVRFNSS HGFPVEVDSD TSIFQLKEVV AKRQGVPADQ LRVIFAGKEL RNDWTVQNCD LDQQSIVHIV QRPWRKGQEM NATGGDDPRN AAGGCEREPQ SLTRVDLSSS VLPGDSVGLA VILHTDSRKD SPPAGSPAGR SIYNSFYVYC KGPCQRVQPG KLRVQCSTCR QATLTLTQGP SCWDDVLIPN RMSGECQSPH CPGTSAEFFF KCGAHPTSDK ETSVALHLIA TNSRNITCIT CTDVRSPVLV FQCNSRHVIC LDCFHLYCVT RLNDRQFVHD PQLGYSLPCV AGCPNSLIKE LHHFRILGEE QYNRYQQYGA EECVLQMGGV LCPRPGCGAG LLPEPDQRKV TCEGGNGLGC GFAFCRECKE AYHEGECSAV FEASGTTTQA YRVDERAAEQ ARWEAASKET IKKTTKPCPR CHVPVEKNGG CMHMKCPQPQ CRLEWCWNCG CEWNRVCMGD HWFDV // ID PSN1_HUMAN Reviewed; 467 AA. AC P49768; B2R6D3; O95465; Q14762; Q15719; Q15720; Q96P33; Q9UIF0; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1996, sequence version 1. DT 28-JAN-2026, entry version 263. DE RecName: Full=Presenilin-1 {ECO:0000303|PubMed:9144240}; DE Short=PS-1 {ECO:0000303|PubMed:9298817}; DE EC=3.4.23.- {ECO:0000269|PubMed:10206644, ECO:0000269|PubMed:10811883, ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:12679784, ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:26280335}; DE AltName: Full=Protein S182 {ECO:0000303|PubMed:7550356}; DE Contains: DE RecName: Full=Presenilin-1 NTF subunit {ECO:0000305|PubMed:9173929}; DE Contains: DE RecName: Full=Presenilin-1 CTF subunit {ECO:0000305|PubMed:9173929}; DE Contains: DE RecName: Full=Presenilin-1 CTF12 {ECO:0000305|PubMed:9485372}; DE Short=PS1-CTF12; GN Name=PSEN1 {ECO:0000312|HGNC:HGNC:9508}; Synonyms=AD3, PS1, PSNL1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 2), VARIANTS AD3 RP LEU-146; ARG-163; GLU-246 AND VAL-286, AND TISSUE SPECIFICITY. RC TISSUE=Brain; RX PubMed=7596406; DOI=10.1038/375754a0; RA Sherrington R., Rogaev E.I., Liang Y., Rogaeva E.A., Levesque G., Ikeda M., RA Chi H., Lin C., Li G., Holman K., Tsuda T., Mar L., Foncin J.-F., RA Bruni A.C., Montesi M.P., Sorbi S., Rainero I., Pinessi L., Nee L., RA Chumakov I., Pollen D., Brookes A., Sanseau P., Polinsky R.J., Wasco W., RA da Silva H.A.R., Haines J.L., Pericak-Vance M.A., Tanzi R.E., Roses A.D., RA Fraser P.E., Rommens J.M., St George-Hyslop P.H.; RT "Cloning of a gene bearing missense mutations in early-onset familial RT Alzheimer's disease."; RL Nature 375:754-760(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), AND TISSUE SPECIFICITY. RC TISSUE=Blood, and Brain; RX PubMed=8641442; DOI=10.1016/0014-5793(96)00054-3; RA Sahara N., Yahagi Y., Takagi H., Kondo T., Okochi M., Usami M., RA Shirasawa T., Mori H.; RT "Identification and characterization of presenilin I-467, I-463 and I- RT 374."; RL FEBS Lett. 381:7-11(1996). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4). RA Powell C.S., Gegg M.E., Palmer M.S.; RT "Human presenilin 1 gene encodes an alternative protein-minilin."; RL Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Rowen L., Madan A., Qin S., Abbasi N., Dors M., Ratcliffe A., Madan A., RA Dickhoff R., Shaffer T., James R., Lasky S., Hood L.; RT "Complete sequence of the gene for presenilin 1."; RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5). RA Kang L., Zhang B., Zhou Y., Peng X., Yuan J., Qiang B.; RL Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Tongue; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12508121; DOI=10.1038/nature01348; RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., RA Waterston R., Hood L., Weissenbach J.; RT "The DNA sequence and analysis of human chromosome 14."; RL Nature 421:601-607(2003). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). 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 [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-113. RX PubMed=9070286; DOI=10.1006/bbrc.1996.6043; RA Tsujimura A., Yasojima K., Hashimoto-Gotoh T.; RT "Cloning of Xenopus presenilin-alpha and -beta cDNAs and their differential RT expression in oogenesis and embryogenesis."; RL Biochem. Biophys. Res. Commun. 231:392-396(1997). RN [11] RP NUCLEOTIDE SEQUENCE [MRNA] OF 24-32, AND ALTERNATIVE SPLICING (ISOFORMS 6 RP AND 7). RC TISSUE=Megakaryocyte, and Platelet; RX PubMed=8804415; DOI=10.1016/0014-5793(96)00845-9; RA Vidal R., Ghiso J., Wisniewski T., Frangione B.; RT "Alzheimer's presenilin 1 gene expression in platelets and megakaryocytes. RT Identification of a novel splice variant."; RL FEBS Lett. 393:19-23(1996). RN [12] RP PROTEIN SEQUENCE OF 36-42; 61-76; 109-129; 217-239; 270-278; 315-320; RP 345-352 AND 381-395 (ISOFORM 1), IDENTIFICATION BY MASS SPECTROMETRY, RP IDENTIFICATION IN GAMMA-SECRETASE COMPLEX, FUNCTION, CATALYTIC ACTIVITY, RP AND SUBCELLULAR LOCATION. RX PubMed=15274632; DOI=10.1021/bi0494976; RA Fraering P.C., Ye W., Strub J.-M., Dolios G., LaVoie M.J., RA Ostaszewski B.L., van Dorsselaer A., Wang R., Selkoe D.J., Wolfe M.S.; RT "Purification and characterization of the human gamma-secretase complex."; RL Biochemistry 43:9774-9789(2004). RN [13] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=8574969; DOI=10.1038/nm0296-224; RA Kovacs D.M., Fausett H.J., Page K.J., Kim T.-W., Moir R.D., Merriam D.E., RA Hollister R.D., Hallmark O.G., Mancini R., Felsenstein K.M., Hyman B.T., RA Tanzi R.E., Wasco W.; RT "Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and RT localization to intracellular membranes in mammalian cells."; RL Nat. Med. 2:224-229(1996). RN [14] RP PROTEOLYTIC PROCESSING. RX PubMed=9173929; DOI=10.1006/nbdi.1997.0129; RA Podlisny M.B., Citron M., Amarante P., Sherrington R., Xia W., Zhang J., RA Diehl T., Levesque G., Fraser P., Haass C., Koo E.H., Seubert P., RA St George-Hyslop P.H., Teplow D.B., Selkoe D.J.; RT "Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 RT and Ala299 and occur as stable N- and C-terminal fragments in normal and RT Alzheimer brain tissue."; RL Neurobiol. Dis. 3:325-337(1997). RN [15] RP PHOSPHORYLATION. RX PubMed=9144240; DOI=10.1073/pnas.94.10.5349; RA Walter J., Gruenberg J., Capell A., Pesold B., Schindzielorz A., Citron M., RA Mendla K., St George-Hyslop P.H., Multhaup G., Selkoe D.J., Haass C.; RT "Proteolytic processing of the Alzheimer disease-associated presenilin-1 RT generates an in vivo substrate for protein kinase C."; RL Proc. Natl. Acad. Sci. U.S.A. 94:5349-5354(1997). RN [16] RP CASPASE CLEAVAGE SITE, AND MUTAGENESIS OF ASP-345; ASP-373 AND ASP-385. RX PubMed=9485372; DOI=10.1021/bi972106l; RA Gruenberg J., Walter J., Loetscher H., Deuschle U., Jacobsen H., Haass C.; RT "Alzheimer's disease associated presenilin-1 holoprotein and its 18-20 kDa RT C-terminal fragment are death substrates for proteases of the caspase RT family."; RL Biochemistry 37:2263-2270(1998). RN [17] RP FUNCTION, INTERACTION WITH CTNNB1, AND SUBCELLULAR LOCATION. RX PubMed=9738936; DOI=10.1016/s0014-5793(98)00886-2; RA Murayama M., Tanaka S., Palacino J., Murayama O., Honda T., Sun X., RA Yasutake K., Nihonmatsu N., Wolozin B., Takashima A.; RT "Direct association of presenilin-1 with beta-catenin."; RL FEBS Lett. 433:73-77(1998). RN [18] RP INTERACTION WITH FLNA AND FLNB. 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 [19] RP FUNCTION, MUTAGENESIS OF MET-292, AND PROTEOLYTIC PROCESSING. RX PubMed=10545183; DOI=10.1021/bi9914210; RA Steiner H., Romig H., Pesold B., Philipp U., Baader M., Citron M., RA Loetscher H., Jacobsen H., Haass C.; RT "Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 RT in the absence of endoproteolysis."; RL Biochemistry 38:14600-14605(1999). RN [20] RP INTERACTION WITH MTCH1. RX PubMed=10551805; DOI=10.1074/jbc.274.46.32543; RA Xu X., Shi Y.-C., Wu X., Gambetti P., Sui D., Cui M.-Z.; RT "Identification of a novel PSD-95/Dlg/ZO-1 (PDZ)-like protein interacting RT with the C terminus of presenilin-1."; RL J. Biol. Chem. 274:32543-32546(1999). RN [21] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH NOTCH. RX PubMed=10593990; DOI=10.1074/jbc.274.51.36801; RA Ray W.J., Yao M., Mumm J., Schroeter E.H., Saftig P., Wolfe M., RA Selkoe D.J., Kopan R., Goate A.M.; RT "Cell surface presenilin-1 participates in the gamma-secretase-like RT proteolysis of Notch."; RL J. Biol. Chem. 274:36801-36807(1999). RN [22] RP INTERACTION WITH CTNND2 AND CTNNB1, AND SUBCELLULAR LOCATION. RX PubMed=10037471; DOI=10.1046/j.1471-4159.1999.0720999.x; RA Levesque G., Yu G., Nishimura M., Zhang D.M., Levesque L., Yu H., Xu D., RA Liang Y., Rogaeva E.A., Ikeda M., Duthie M., Murgolo N., Wang L., RA VanderVere P., Bayne M.L., Strader C.D., Rommens J.M., Fraser P.E., RA St George-Hyslop P.H.; RT "Presenilins interact with armadillo proteins including neural-specific RT plakophilin-related protein and beta-catenin."; RL J. Neurochem. 72:999-1008(1999). RN [23] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF ASP-257 AND RP ASP-385. RX PubMed=10206644; DOI=10.1038/19077; RA Wolfe M.S., Xia W., Ostaszewski B.L., Diehl T.S., Kimberly W.T., RA Selkoe D.J.; RT "Two transmembrane aspartates in presenilin-1 required for presenilin RT endoproteolysis and gamma-secretase activity."; RL Nature 398:513-517(1999). RN [24] RP INTERACTION WITH DOCK3. RX PubMed=10854253; DOI=10.1046/j.1471-4159.2000.0750109.x; RA Kashiwa A., Yoshida H., Lee S., Paladino T., Liu Y., Chen Q., Dargusch R., RA Schubert D., Kimura H.; RT "Isolation and characterization of novel presenilin binding protein."; RL J. Neurochem. 75:109-116(2000). RN [25] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF ASP-257 AND RP ASP-385. RX PubMed=10899933; DOI=10.1046/j.1471-4159.2000.0750583.x; RA Berezovska O., Jack C., McLean P., Aster J.C., Hicks C., Xia W., RA Wolfe M.S., Kimberly W.T., Weinmaster G., Selkoe D.J., Hyman B.T.; RT "Aspartate mutations in presenilin and gamma-secretase inhibitors both RT impair notch1 proteolysis and nuclear translocation with relative RT preservation of notch1 signaling."; RL J. Neurochem. 75:583-593(2000). RN [26] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF LEU-286. RX PubMed=10811883; DOI=10.1073/pnas.100049897; RA Kulic L., Walter J., Multhaup G., Teplow D.B., Baumeister R., Romig H., RA Capell A., Steiner H., Haass C.; RT "Separation of presenilin function in amyloid beta-peptide generation and RT endoproteolysis of Notch."; RL Proc. Natl. Acad. Sci. U.S.A. 97:5913-5918(2000). RN [27] RP INTERACTION WITH PARL. RX PubMed=12214059; DOI=10.3233/jad-2001-3203; RA Pellegrini L., Passer B.J., Canelles M., Lefterov I., Ganjei J.K., RA Fowlkes B.J., Koonin E.V., D'Adamio L.; RT "PAMP and PARL, two novel putative metalloproteases interacting with the RT COOH-terminus of presenilin-1 and -2."; RL J. Alzheimers Dis. 3:181-190(2001). RN [28] RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=11987239; DOI=10.1006/bcmd.2002.0486; RA Mirinics Z.K., Calafat J., Udby L., Lovelock J., Kjeldsen L., RA Rothermund K., Sisodia S.S., Borregaard N., Corey S.J.; RT "Identification of the presenilins in hematopoietic cells with localization RT of presenilin 1 to neutrophil and platelet granules."; RL Blood Cells Mol. Dis. 28:28-38(2002). RN [29] RP FUNCTION, SUBCELLULAR LOCATION, AND IDENTIFICATION IN A COMPLEX WITH CDH1 RP AND CTNNB1. RX PubMed=11953314; DOI=10.1093/emboj/21.8.1948; RA Marambaud P., Shioi J., Serban G., Georgakopoulos A., Sarner S., Nagy V., RA Baki L., Wen P., Efthimiopoulos S., Shao Z., Wisniewski T., Robakis N.K.; RT "A presenilin-1/gamma-secretase cleavage releases the E-cadherin RT intracellular domain and regulates disassembly of adherens junctions."; RL EMBO J. 21:1948-1956(2002). RN [30] RP INTERACTION WITH HERPUD1. RX PubMed=11799129; DOI=10.1074/jbc.m112372200; RA Sai X., Kawamura Y., Kokame K., Yamaguchi H., Shiraishi H., Suzuki R., RA Suzuki T., Kawaichi M., Miyata T., Kitamura T., De Strooper B., RA Yanagisawa K., Komano H.; RT "Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin- RT mediated generation of amyloid beta-protein."; RL J. Biol. Chem. 277:12915-12920(2002). RN [31] RP INTERACTION WITH GFAP, MUTAGENESIS OF 66-ASP--ASP-72; 76-LYS-TYR-77; RP 82-VAL-ILE-83; VAL-82 AND 84-MET-LEU-85, AND CHARACTERIZATION OF VARIANTS RP AD3 VAL-79 AND LEU-82. RX PubMed=12058025; DOI=10.1074/jbc.m112121200; RA Nielsen A.L., Holm I.E., Johansen M., Bonven B., Jorgensen P., RA Jorgensen A.L.; RT "A new splice variant of glial fibrillary acidic protein GFAPepsilon, RT interacts with the presenilin proteins."; RL J. Biol. Chem. 277:29983-29991(2002). RN [32] RP INTERACTION WITH CDH2, SUBCELLULAR LOCATION, AND MUTAGENESIS OF ASP-385. RX PubMed=14515347; DOI=10.1002/jnr.10753; RA Uemura K., Kitagawa N., Kohno R., Kuzuya A., Kageyama T., Chonabayashi K., RA Shibasaki H., Shimohama S.; RT "Presenilin 1 is involved in maturation and trafficking of N-cadherin to RT the plasma membrane."; RL J. Neurosci. Res. 74:184-191(2003). RN [33] RP ENZYME ACTIVITY OF A GAMMA-SECRETASE COMPLEX, CATALYTIC ACTIVITY, FUNCTION, RP AND SUBUNIT. RX PubMed=12679784; DOI=10.1038/ncb960; RA Edbauer D., Winkler E., Regula J.T., Pesold B., Steiner H., Haass C.; RT "Reconstitution of gamma-secretase activity."; RL Nat. Cell Biol. 5:486-488(2003). RN [34] RP COMPONENT OF A GAMMA-SECRETASE COMPLEX WITH PEN2; PSEN1/PSEN2 AND NCSTN. RX PubMed=12740439; DOI=10.1073/pnas.1037392100; RA Kimberly W.T., LaVoie M.J., Ostaszewski B.L., Ye W., Wolfe M.S., RA Selkoe D.J.; RT "Gamma-secretase is a membrane protein complex comprised of presenilin, RT nicastrin, Aph-1, and Pen-2."; RL Proc. Natl. Acad. Sci. U.S.A. 100:6382-6387(2003). RN [35] RP SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S). RX PubMed=14759258; DOI=10.1186/gb-2004-5-2-r8; RA Hillman R.T., Green R.E., Brenner S.E.; RT "An unappreciated role for RNA surveillance."; RL Genome Biol. 5:R8.1-R8.16(2004). RN [36] RP FUNCTION, SUBCELLULAR LOCATION, VARIANT AD3 SER-117, AND CHARACTERIZATION RP OF VARIANTS AD3 LEU-117 AND SER-117. RX PubMed=15004326; DOI=10.3233/jad-2004-6105; RA Dowjat W.K., Kuchna I., Wisniewski T., Wegiel J.; RT "A novel highly pathogenic Alzheimer presenilin-1 mutation in codon 117 RT (Pro117Ser): Comparison of clinical, neuropathological and cell culture RT phenotypes of Pro117Leu and Pro117Ser mutations."; RL J. Alzheimers Dis. 6:31-43(2004). RN [37] RP PHOSPHORYLATION AT SER-310 AND SER-346, AND MUTAGENESIS OF SER-310 AND RP SER-346. RX PubMed=14576165; DOI=10.1074/jbc.m306653200; RA Fluhrer R., Friedlein A., Haass C., Walter J.; RT "Phosphorylation of presenilin 1 at the caspase recognition site regulates RT its proteolytic processing and the progression of apoptosis."; RL J. Biol. Chem. 279:1585-1593(2004). RN [38] RP TOPOLOGY. RX PubMed=15385547; DOI=10.1074/jbc.m407898200; RA Friedmann E., Lemberg M.K., Weihofen A., Dev K.K., Dengler U., Rovelli G., RA Martoglio B.; RT "Consensus analysis of signal peptide peptidase and homologous human RT aspartic proteases reveals opposite topology of catalytic domains compared RT with presenilins."; RL J. Biol. Chem. 279:50790-50798(2004). RN [39] RP FUNCTION, ACTIVE SITES ASP-257 AND ASP-385, AND MUTAGENESIS OF TYR-256; RP ASP-257; ASP-385 AND TYR-389. RX PubMed=15341515; DOI=10.1111/j.1471-4159.2004.02596.x; RA Wrigley J.D., Nunn E.J., Nyabi O., Clarke E.E., Hunt P., Nadin A., RA De Strooper B., Shearman M.S., Beher D.; RT "Conserved residues within the putative active site of gamma-secretase RT differentially influence enzyme activity and inhibitor binding."; RL J. Neurochem. 90:1312-1320(2004). RN [40] RP INTERACTION WITH CDH1 AND CTNNB1. RX PubMed=16126725; DOI=10.1074/jbc.m507503200; RA Serban G., Kouchi Z., Baki L., Georgakopoulos A., Litterst C.M., Shioi J., RA Robakis N.K.; RT "Cadherins mediate both the association between PS1 and beta-catenin and RT the effects of PS1 on beta-catenin stability."; RL J. Biol. Chem. 280:36007-36012(2005). RN [41] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [42] RP FUNCTION, AND CHARACTERIZATION OF VARIANT AD3 VAL-146. RX PubMed=16959576; DOI=10.1016/j.cell.2006.06.059; RA Tu H., Nelson O., Bezprozvanny A., Wang Z., Lee S.F., Hao Y.H., RA Serneels L., De Strooper B., Yu G., Bezprozvanny I.; RT "Presenilins form ER Ca2+ leak channels, a function disrupted by familial RT Alzheimer's disease-linked mutations."; RL Cell 126:981-993(2006). RN [43] RP FUNCTION OF PAL MOTIF, MUTAGENESIS OF PRO-433; ALA-434 AND LEU-435, AND RP CHARACTERIZATION OF VARIANT AD3 PHE-435. RX PubMed=16305624; DOI=10.1111/j.1471-4159.2005.03548.x; RA Wang J., Beher D., Nyborg A.C., Shearman M.S., Golde T.E., Goate A.; RT "C-terminal PAL motif of presenilin and presenilin homologues required for RT normal active site conformation."; RL J. Neurochem. 96:218-227(2006). RN [44] RP VARIANTS AD3 ILE-139 AND CYS-289. RX PubMed=8875251; DOI=10.1093/hmg/5.supplement_1.1449; RA Cruts M., Hendriks L., Van Broeckhoven C.; RT "The presenilin genes: a new gene family involved in Alzheimer disease RT pathology."; RL Hum. Mol. Genet. 5:1449-1455(1996). RN [45] RP REVIEW ON VARIANTS. RX PubMed=9521418; RX DOI=10.1002/(sici)1098-1004(1998)11:3<183::aid-humu1>3.0.co;2-j; RA Cruts M., van Broeckhoven C.; RT "Presenilin mutations in Alzheimer's disease."; RL Hum. Mutat. 11:183-190(1998). RN [46] 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 [47] 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 [48] 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 [49] RP IDENTIFICATION IN THE GAMMA-SECRETASE COMPLEX, AND INTERACTION WITH CRB2. RX PubMed=20299451; DOI=10.1074/jbc.m109.038760; RA Mitsuishi Y., Hasegawa H., Matsuo A., Araki W., Suzuki T., Tagami S., RA Okochi M., Takeda M., Roepman R., Nishimura M.; RT "Human CRB2 inhibits gamma-secretase cleavage of amyloid precursor protein RT by binding to the presenilin complex."; RL J. Biol. Chem. 285:14920-14931(2010). RN [50] 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 [51] RP INVOLVEMENT IN ACNINV3. RX PubMed=20929727; DOI=10.1126/science.1196284; RA Wang B., Yang W., Wen W., Sun J., Su B., Liu B., Ma D., Lv D., Wen Y., RA Qu T., Chen M., Sun M., Shen Y., Zhang X.; RT "Gamma-secretase gene mutations in familial acne inversa."; RL Science 330:1065-1065(2010). RN [52] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43 AND SER-367, AND 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 [53] RP SUBCELLULAR LOCATION, AND INTERACTION WITH UBQLN1. RX PubMed=21143716; DOI=10.1111/j.1600-0854.2010.01149.x; RA Viswanathan J., Haapasalo A., Bottcher C., Miettinen R., Kurkinen K.M., RA Lu A., Thomas A., Maynard C.J., Romano D., Hyman B.T., Berezovska O., RA Bertram L., Soininen H., Dantuma N.P., Tanzi R.E., Hiltunen M.; RT "Alzheimer's disease-associated ubiquilin-1 regulates presenilin-1 RT accumulation and aggresome formation."; RL Traffic 12:330-348(2011). RN [54] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43 AND SER-367, AND RP IDENTIFICATION BY 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 [55] RP FUNCTION, INTERACTION WITH APH1A/APH1B AND PEN2, SUBCELLULAR LOCATION, AND RP CHARACTERIZATION OF VARIANT AD3 ASP-206. RX PubMed=25394380; DOI=10.1007/s12035-014-8969-1; RA Chen W.T., Hsieh Y.F., Huang Y.J., Lin C.C., Lin Y.T., Liu Y.C., Lien C.C., RA Cheng I.H.; RT "G206D mutation of presenilin-1 reduces Pen2 interaction, increases RT Abeta42/Abeta40 ratio and elevates ER Ca(2+) accumulation."; RL Mol. Neurobiol. 52:1835-1849(2015). RN [56] {ECO:0007744|PDB:2KR6} RP STRUCTURE BY NMR OF 292-467. RA Doetsch V.; RT "Solution structure of presenilin-1 CTF subunit."; RL Submitted (DEC-2009) to the PDB data bank. RN [57] RP STRUCTURE BY ELECTRON MICROSCOPY (4.5 ANGSTROMS), FUNCTION, SUBCELLULAR RP LOCATION, SUBUNIT, AND TOPOLOGY. RX PubMed=25043039; DOI=10.1038/nature13567; RA Lu P., Bai X.C., Ma D., Xie T., Yan C., Sun L., Yang G., Zhao Y., Zhou R., RA Scheres S.H., Shi Y.; RT "Three-dimensional structure of human gamma-secretase."; RL Nature 512:166-170(2014). RN [58] {ECO:0007744|PDB:5FN2, ECO:0007744|PDB:5FN3, ECO:0007744|PDB:5FN4, ECO:0007744|PDB:5FN5} RP STRUCTURE BY ELECTRON MICROSCOPY (4.00 ANGSTROMS), SUBUNIT, AND TOPOLOGY. RX PubMed=26623517; DOI=10.7554/elife.11182; RA Bai X.C., Rajendra E., Yang G., Shi Y., Scheres S.H.; RT "Sampling the conformational space of the catalytic subunit of human gamma- RT secretase."; RL Elife 4:0-0(2015). RN [59] {ECO:0007744|PDB:5A63} RP STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, RP TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF RP VARIANTS AD3 LEU-213; ILE-237 AND PHE-261, AND MUTAGENESIS OF ILE-202; RP LEU-226; LEU-248 AND LEU-424. RX PubMed=26280335; DOI=10.1038/nature14892; RA Bai X.C., Yan C., Yang G., Lu P., Ma D., Sun L., Zhou R., Scheres S.H., RA Shi Y.; RT "An atomic structure of human gamma-secretase."; RL Nature 525:212-217(2015). RN [60] {ECO:0007744|PDB:4UIS} RP STRUCTURE BY ELECTRON MICROSCOPY (4.40 ANGSTROMS) OF 81-463, SUBUNIT, AND RP TOPOLOGY. RX PubMed=25918421; DOI=10.1073/pnas.1506242112; RA Sun L., Zhao L., Yang G., Yan C., Zhou R., Zhou X., Xie T., Zhao Y., Wu S., RA Li X., Shi Y.; RT "Structural basis of human gamma-secretase assembly."; RL Proc. Natl. Acad. Sci. U.S.A. 112:6003-6008(2015). RN [61] RP STRUCTURE BY ELECTRON MICROSCOPY (2.70 ANGSTROMS) OF MUTANT ALA-385 IN RP COMPLEX WITH NOTCH1; PSENEN; APH1A AND NCSTN, SUBUNIT, TOPOLOGY, CATALYTIC RP ACTIVITY, FUNCTION, ACTIVE SITE, MUTAGENESIS OF GLN-112; 288-TYR--SER-290; RP 377-ARG--LEU-381; ASP-385; LEU-432 AND 432-LEU--ALA-434, AND DOMAIN. RX PubMed=30598546; DOI=10.1038/s41586-018-0813-8; RA Yang G., Zhou R., Zhou Q., Guo X., Yan C., Ke M., Lei J., Shi Y.; RT "Structural basis of Notch recognition by human gamma-secretase."; RL Nature 565:192-197(2019). RN [62] RP STRUCTURE BY ELECTRON MICROSCOPY (2.60 ANGSTROMS) OF MUTANT ALA-385 IN RP COMPLEX WITH APP CHAIN C83; PSENEN; APH1A AND NCSTN, SUBUNIT, TOPOLOGY, RP CATALYTIC ACTIVITY, FUNCTION, ACTIVE SITE, DOMAIN, AND MUTAGENESIS OF RP GLN-112; 288-TYR--SER-290; 377-ARG--LEU-381; ASP-385; LEU-432 AND RP 432-LEU--ALA-434. RX PubMed=30630874; DOI=10.1126/science.aaw0930; RA Zhou R., Yang G., Guo X., Zhou Q., Lei J., Shi Y.; RT "Recognition of the amyloid precursor protein by human gamma-secretase."; RL Science 0:0-0(2019). RN [63] RP VARIANTS AD3 THR-143 AND ALA-384. RX PubMed=8634711; DOI=10.1093/hmg/4.12.2363; RA Cruts M., Backhovens H., Wang S.-Y., van Gassen G., Theuns J., RA de Jonghe C., Wehnert A., de Voecht J., de Winter G., Cras P., Bruyland M., RA Datson N., Weissenbach J., den Dunnen J.T., Martin J.-J., Hendriks L., RA Van Broeckhoven C.; RT "Molecular genetic analysis of familial early-onset Alzheimer's disease RT linked to chromosome 14q24.3."; RL Hum. Mol. Genet. 4:2363-2372(1995). RN [64] RP VARIANTS AD3 LEU-82; HIS-115; THR-139; ARG-163; THR-231; LEU-264; VAL-392 RP AND TYR-410. RX PubMed=8634712; DOI=10.1093/hmg/4.12.2373; RA Campion D., Flaman J.-M., Brice A., Hannequin D., Dubois B., Martin C., RA Moreau V., Charbonnier F., Didierjean O., Tardieu S., Penet C., Puel M., RA Pasquier F., le Doze F., Bellis G., Calenda A., Heilig R., Martinez M., RA Mallet J., Bellis M., Clerget-Darpoux F., Agid Y., Frebourg T.; RT "Mutations of the presenilin I gene in families with early-onset RT Alzheimer's disease."; RL Hum. Mol. Genet. 4:2373-2377(1995). RN [65] RP VARIANTS AD3 VAL-260; VAL-285 AND VAL-392. RX PubMed=7651536; DOI=10.1038/376775a0; RA Rogaev E.I., Sherrington R., Rogaeva E.A., Levesque G., Ikeda M., Liang Y., RA Chi H., Lin C., Holman K., Tsuda T., Mar L., Sorbi S., Nacmias B., RA Piacentini S., Amaducci L., Chumakov I., Cohen D., Lannfelt L., RA Fraser P.E., Rommens J.M., St George-Hyslop P.H.; RT "Familial Alzheimer's disease in kindreds with missense mutations in a gene RT on chromosome 1 related to the Alzheimer's disease type 3 gene."; RL Nature 376:775-778(1995). RN [66] RP VARIANTS AD3 VAL-139; VAL-146; TYR-163; SER-267; ALA-280 AND GLY-280. RX PubMed=7550356; DOI=10.1038/ng1095-219; RA Clark R.F., Hutton M., Fuldner R.A., Froelich S., Karran E., Talbot C., RA Crook R., Lendon C.L., Prihar G., He C., Korenblat K., Martinez A., RA Wragg M., Busfield F., Behrens M.I., Myers A., Norton J., Morris J., RA Mehta N., Pearson C., Lincoln S., Baker M., Duff K., Zehr C., Perez-Tur J., RA Houlden H., Ruiz A., Ossa J., Lopera F., Arcos M., Madrigal L., RA Collinge J., Humphreys C., Asworth T., Sarner S., Fox N.C., Harvey R., RA Kennedy A., Roques P.K., Cline R.T., Phillips C.A., Venter J.C., Forsel L., RA Axelman K., Lilius L., Johnston J., Cowburn R., Viitanen M., Winblad B., RA Kosik K.S., Haltia M., Poyhonen M., Dickson D., Mann D., Neary D., RA Snowden J., Lantos P., Lannfelt L., Rossor M.N., Roberts G.W., Adams M.D., RA Hardy J., Goate A.M.; RT "The structure of the presenilin 1 (S182) gene and identification of six RT novel mutations in early onset AD families."; RL Nat. Genet. 11:219-222(1995). RN [67] RP VARIANT AD3 ALA-280, AND INVOLVEMENT IN AD3. RX PubMed=8837617; DOI=10.1038/nm1096-1146; RA Lemere C.A., Lopera F., Kosik K.S., Lendon C.L., Ossa J., Saido T.C., RA Yamaguchi H., Ruiz A., Martinez A., Madrigal L., Hincapie L., Arango J.C., RA Anthony D.C., Koo E.H., Goate A.M., Selkoe D.J., Arango J.C.; RT "The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 RT deposition and severe cerebellar pathology."; RL Nat. Med. 2:1146-1150(1996). RN [68] RP VARIANTS AD3 PHE-96; ARG-163 AND THR-213. RX PubMed=8733303; DOI=10.1016/0304-3940(96)12587-8; RA Kamino K., Sato S., Sakaki Y., Yoshiiwa A., Nishiwaki Y., Takeda H., RA Tanabe H., Nishimura T., Li K., St George-Hyslop P.H., Miki T., Ogihara T.; RT "Three different mutations of presenilin 1 gene in early-onset Alzheimer's RT disease families."; RL Neurosci. Lett. 208:195-198(1996). RN [69] RP VARIANT AD3 ASP-135. RX PubMed=9225696; DOI=10.1002/ana.410420121; RA Crook R., Ellis R., Shanks M., Thal L.J., Perez-Tur J., Baker M., RA Hutton M., Haltia T., Hardy J., Galasko D.; RT "Early-onset Alzheimer's disease with a presenilin-1 mutation at the site RT corresponding to the Volga German presenilin-2 mutation."; RL Ann. Neurol. 42:124-128(1997). RN [70] RP VARIANT AD3 ALA-280. RX PubMed=9298817; RX DOI=10.1002/(sici)1098-1004(1997)10:3<186::aid-humu2>3.0.co;2-h; RA Lendon C.L., Martinez A., Behrens I.M., Kosik K.S., Madrigal L., Norton J., RA Neuman R., Myers A., Busfield F., Wragg M., Arcos M., Arango-Viana J.C., RA Ossa J., Ruiz A., Goate A.M., Lopera F.; RT "E280A PS-1 mutation causes Alzheimer's disease but age of onset is not RT modified by ApoE alleles."; RL Hum. Mutat. 10:186-195(1997). RN [71] RP VARIANTS AD3 THR-233 AND THR-278. RX PubMed=9172170; DOI=10.1097/00001756-199704140-00043; RA Kwok J.B.J., Taddei K., Hallupp M., Fisher C., Brooks W.S., Broe G.A., RA Hardy J., Fulham M.J., Nicholson G.A., Stell R., St George-Hyslop P.H., RA Fraser P.E., Kakulas B., Clarnette R., Relkin N., Gandy S.E., RA Schofield P.R., Martins R.N.; RT "Two novel (M233T and R278T) presenilin-1 mutations in early-onset RT Alzheimer's disease pedigrees and preliminary evidence for association of RT presenilin-1 mutations with a novel phenotype."; RL NeuroReport 8:1537-1542(1997). RN [72] RP VARIANT AD3 PRO-171. RX PubMed=9833068; RA Ramirez-Duenas M.G., Rogaeva E.A., Leal C.A., Lin C., RA Ramirez-Casillas G.A., Hernandez-Romo J.A., St George-Hyslop P.H., RA Cantu J.M.; RT "A novel Leu171Pro mutation in presenilin-1 gene in a Mexican family with RT early onset Alzheimer disease."; RL Ann. Genet. 41:149-153(1998). RN [73] RP VARIANT GLY-318. RX PubMed=9851443; DOI=10.1002/ana.410440617; RA Mattila K.M., Forsell C., Pirttila T., Rinne J.O., Lehtimaki T., Roytta M., RA Lilius L., Eerola A., St George-Hyslop P.H., Frey H., Lannfelt L.; RT "The Glu318Gly mutation of the presenilin-1 gene does not necessarily cause RT Alzheimer's disease."; RL Ann. Neurol. 44:965-967(1998). RN [74] RP VARIANT GLY-318. RX PubMed=9851450; DOI=10.1002/ana.410440624; RA Aldudo J., Bullido M.J., Frank A., Valdivieso F.; RT "Missense mutation E318G of the presenilin-1 gene appears to be a RT nonpathogenic polymorphism."; RL Ann. Neurol. 44:985-986(1998). RN [75] RP VARIANTS AD3 VAL-79; CYS-115 AND VAL-231, AND VARIANT GLY-318. RX PubMed=9384602; DOI=10.1093/hmg/7.1.43; RA Cruts M., van Duijn C.M., Backhovens H., van den Broeck M., Wehnert A., RA Serneels S., Sherrington R., Hutton M., Hardy J., St George-Hyslop P.H., RA Hofman A., van Broeckhoven C.; RT "Estimation of the genetic contribution of presenilin-1 and -2 mutations in RT a population-based study of presenile Alzheimer disease."; RL Hum. Mol. Genet. 7:43-51(1998). RN [76] RP VARIANTS AD3 ASP-120; ARG-163; VAL-209; VAL-260; LEU-264; TYR-410 AND RP PRO-426. RX PubMed=9521423; RX DOI=10.1002/(sici)1098-1004(1998)11:3<216::aid-humu6>3.0.co;2-f; RA Poorkaj P., Sharma V., Anderson L., Nemens E., Alonso M.E., Orr H., RA White J., Heston L., Bird T.D., Schellenberg G.D.; RT "Missense mutations in the chromosome 14 familial Alzheimer's disease RT presenilin 1 gene."; RL Hum. Mutat. 11:216-221(1998). RN [77] RP VARIANT AD3 GLU-378. RX PubMed=10200054; RX DOI=10.1002/(sici)1098-1004(1998)11:6<481::aid-humu12>3.0.co;2-q; RA Besancon R., Lorenzi A., Cruts M., Radawiec S., Sturtz F., Broussolle E., RA Chazot G., van Broeckhoven C., Chamba G., Vandenberghe A.; RT "Missense mutation in exon 11 (codon 378) of the presenilin-1 gene in a RT French family with early-onset Alzheimer's disease and transmission study RT by mismatch enhanced allele specific amplification."; RL Hum. Mutat. 11:481-481(1998). RN [78] RP VARIANT AD3 LYS-139. RX PubMed=9719376; DOI=10.1136/jmg.35.8.672; RA Dumanchin C., Brice A., Campion D., Hannequin D., Martin C., Moreau V., RA Agid Y., Martinez M., Clerget-Darpoux F., Frebourg T.; RT "De novo presenilin 1 mutations are rare in clinically sporadic, early RT onset Alzheimer's disease cases."; RL J. Med. Genet. 35:672-673(1998). RN [79] RP VARIANT AD3 LEU-117. RX PubMed=9507958; DOI=10.1097/00001756-199801260-00008; RA Wisniewski T., Dowjat W.K., Buxbaum J.D., Khorkova O., Efthimiopoulos S., RA Kulczycki J., Lojkowska W., Wegiel J., Wisniewski H.M., Frangione B.; RT "A novel Polish presenilin-1 mutation (P117L) is associated with familial RT Alzheimer's disease and leads to death as early as the age of 28 years."; RL NeuroReport 9:217-221(1998). RN [80] RP VARIANTS AD3 LEU-169 AND GLN-436. RX PubMed=9831473; DOI=10.1097/00001756-199810050-00034; RA Taddei K., Kwok J.B., Kril J.J., Halliday G.M., Creasey H., Hallupp M., RA Fisher C., Brooks W.S., Chung C., Andrews C., Masters C.L., Schofield P.R., RA Martins R.N.; RT "Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with RT very early onset Alzheimer's disease."; RL NeuroReport 9:3335-3339(1998). RN [81] RP VARIANT GLY-318. RX PubMed=9915968; DOI=10.1086/302200; RA Dermaut B., Cruts M., Slooter A.J.C., van Gestel S., de Jonghe C., RA Vanderstichele H., Vanmechelen E., Breteler M.M., Hofman A., RA van Duijn C.M., van Broeckhoven C.; RT "The Glu318Gly substitution in presenilin 1 is not causally related to RT Alzheimer disease."; RL Am. J. Hum. Genet. 64:290-292(1999). RN [82] RP VARIANTS AD3 LEU-82; HIS-115; ASP-120; THR-139; LEU-146; ILE-147; ARG-163; RP CYS-165; TRP-173; THR-231; THR-233; PRO-235; LEU-264; ILE-390; VAL-392 AND RP TYR-410, AND VARIANT GLY-318. RX PubMed=10441572; DOI=10.1086/302553; RA Campion D., Dumanchin C., Hannequin D., Dubois B., Belliard S., Puel M., RA Thomas-Anterion C., Michon A., Martin C., Charbonnier F., Raux G., RA Camuzat A., Penet C., Mesnage V., Martinez M., Clerget-Darpoux F., RA Brice A., Frebourg T.; RT "Early-onset autosomal dominant Alzheimer disease: prevalence, genetic RT heterogeneity, and mutation spectrum."; RL Am. J. Hum. Genet. 65:664-670(1999). RN [83] RP VARIANTS AD3 PHE-143 AND SER-436. RX PubMed=10090481; RX DOI=10.1002/(sici)1098-1004(1999)13:3<256::aid-humu11>3.0.co;2-p; RA Palmer M.S., Beck J.A., Campbell T.A., Humphries C.B., Roques P.K., RA Fox N.C., Harvey R., Rossor M.N., Collinge J.; RT "Pathogenic presenilin 1 mutations (P436S and I143F) in early-onset RT Alzheimer's disease in the UK."; RL Hum. Mutat. 13:256-256(1999). RN [84] RP VARIANT AD3 ARG-209. RX PubMed=10447269; RX DOI=10.1002/(sici)1098-1004(1999)14:1<90::aid-humu19>3.0.co;2-s; RA Sugiyama N., Suzuki K., Matsumura T., Kawanishi C., Onishi H., Yamada Y., RA Iseki E., Kosaka K.; RT "A novel missense mutation (G209R) in exon 8 of the presenilin 1 gene in a RT Japanese family with presenile familial Alzheimer's disease."; RL Hum. Mutat. 14:90-90(1999). RN [85] RP VARIANTS AD3 LEU-233; ARG-282 AND THR-409, AND VARIANT GLY-318. RX PubMed=10533070; RX DOI=10.1002/(sici)1098-1004(199911)14:5<433::aid-humu10>3.0.co;2-k; RA Aldudo J., Bullido M.J., Valdivieso F.; RT "DGGE method for the mutational analysis of the coding and proximal RT promoter regions of the Alzheimer's disease presenilin-1 gene: two novel RT mutations."; RL Hum. Mutat. 14:433-439(1999). RN [86] RP VARIANT AD3 PRO-169. RX PubMed=10025789; DOI=10.1212/wnl.52.3.566; RA Ezquerra M., Carnero C., Blesa R., Gelpi J.L., Ballesta F., Oliva R.; RT "A presenilin 1 mutation (Ser169Pro) associated with early-onset AD and RT myoclonic seizures."; RL Neurology 52:566-570(1999). RN [87] RP VARIANT AD3 PRO-219. RX PubMed=10208579; DOI=10.1097/00001756-199902250-00011; RA Smith M.J., Gardner R.J., Knight M.A., Forrest S.M., Beyreuther K., RA Storey E., McLean C.A., Cotton R.G., Cappal R., Masters C.L.; RT "Early-onset Alzheimer's disease caused by a novel mutation at codon 219 of RT the presenilin-1 gene."; RL NeuroReport 10:503-507(1999). RN [88] RP VARIANT AD3 ASN-116. RX PubMed=10439444; DOI=10.1097/00001756-199908020-00006; RA Romero I., Joergensen P., Bolwig G., Fraser P.E., Rogaeva E., Mann D., RA Havsager A.-M., Joergensen A.L.; RT "A presenilin-1 Thr116Asn substitution in a family with early-onset RT Alzheimer's disease."; RL NeuroReport 10:2255-2260(1999). RN [89] RP VARIANTS AD3 VAL-79; LEU-105 AND VAL-139, AND VARIANT GLY-318. RX PubMed=10631141; DOI=10.1086/302702; RA Finckh U., Mueller-Thomsen T., Mann U., Eggers C., Marksteiner J., RA Meins W., Binetti G., Alberici A., Hock C., Nitsch R.M., Gal A.; RT "High prevalence of pathogenic mutations in patients with early-onset RT dementia detected by sequence analyses of four different genes."; RL Am. J. Hum. Genet. 66:110-117(2000). RN [90] RP VARIANT AD3 SER-405. RX PubMed=10644793; DOI=10.1136/jnnp.68.2.220; RA Yasuda M., Maeda S., Kawamata T., Tamaoka A., Yamamoto Y., Kuroda S., RA Maeda K., Tanaka C.; RT "Novel presenilin-1 mutation with widespread cortical amyloid deposition RT but limited cerebral amyloid angiopathy."; RL J. Neurol. Neurosurg. Psych. 68:220-223(2000). RN [91] RP VARIANT AD3 SER-92. RX PubMed=11027672; DOI=10.1006/bbrc.2000.3646; RA Lewis P.A., Perez-Tur J., Golde T.E., Hardy J.; RT "The presenilin 1 C92S mutation increases abeta 42 production."; RL Biochem. Biophys. Res. Commun. 277:261-263(2000). RN [92] RP VARIANT FTD1 PRO-113. RX PubMed=11094121; DOI=10.1212/wnl.55.10.1577; RA Raux G., Gantier R., Thomas-Anterion C., Boulliat J., Verpillat P., RA Hannequin D., Brice A., Frebourg T., Campion D.; RT "Dementia with prominent frontotemporal features associated with L113P RT presenilin 1 mutation."; RL Neurology 55:1577-1578(2000). RN [93] RP VARIANTS AD3 MET-94; THR-143 AND ALA-280, AND VARIANT GLY-318. RX PubMed=11568920; RX DOI=10.1002/1096-8628(20011001)103:2<138::aid-ajmg1529>3.0.co;2-8; RA Arango D., Cruts M., Torres O., Backhovens H., Serrano M.L., Villareal E., RA Montanes P., Matallana D., Cano C., Van Broeckhoven C., Jacquier M.; RT "Systematic genetic study of Alzheimer disease in Latin America: mutation RT frequencies of the amyloid beta precursor protein and presenilin genes in RT Colombia."; RL Am. J. Med. Genet. 103:138-143(2001). RN [94] RP VARIANT AD3 VAL-282, AND CHARACTERIZATION OF VARIANT AD3 VAL-282. RX PubMed=11701593; DOI=10.1093/brain/124.12.2383; RA Dermaut B., Kumar-Singh S., De Jonghe C., Cruts M., Loefgren A., Luebke U., RA Cras P., Dom R., De Deyn P.P., Martin J.J., Van Broeckhoven C.; RT "Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease RT due to a novel presenilin 1 mutation."; RL Brain 124:2383-2392(2001). RN [95] RP ERRATUM OF PUBMED:11701593, AND VARIANT AD3 GLU-431. RA Ringman J.M., Jain V., Murrell J., Ghetti B., Cochran E.J.; RL Hum. Genet. 109:242-242(2001). RN [96] RP VARIANT AD3 ALA-206. RX PubMed=11710891; DOI=10.1001/jama.286.18.2257; RA Athan E.S., Williamson J., Ciappa A., Santana V., Romas S.N., Lee J.H., RA Rondon H., Lantigua R.A., Medrano M., Torres M., Arawaka S., Rogaeva E., RA Song Y.-Q., Sato C., Kawarai T., Fafel K.C., Boss M.A., Seltzer W.K., RA Stern Y., St George-Hyslop P.H., Tycko B., Mayeux R.; RT "A founder mutation in presenilin 1 causing early-onset Alzheimer disease RT in unrelated Caribbean Hispanic families."; RL JAMA 286:2257-2263(2001). RN [97] RP VARIANT AD3 ILE-237. RX PubMed=11561050; DOI=10.1136/jnnp.71.4.556; RA Sodeyama N., Iwata T., Ishikawa K., Mizusawa H., Yamada M., Itoh Y., RA Otomo E., Matsushita M., Komatsuzaki Y.; RT "Very early onset Alzheimer's disease with spastic paraparesis associated RT with a novel presenilin 1 mutation (Phe237Ile)."; RL J. Neurol. Neurosurg. Psych. 71:556-557(2001). RN [98] RP VARIANTS AD3 GLN-35; VAL-79; CYS-115; ASN-116; THR-143; ILE-146; LEU-146; RP VAL-146; TYR-156 DELINS PHE-THR-TYR; ARG-163; LEU-177; SER-177; PRO-178; RP ALA-206; SER-206; GLU-209; LEU-213; ARG-222; THR-231; LEU-233; PRO-235; RP PHE-261; ARG-274; ARG-352 INS; ILE-354; GLN-358; TYR-365; VAL-394; PHE-418; RP GLU-431; PHE-435 AND VAL-439, AND VARIANT GLY-318. RX PubMed=11524469; DOI=10.1212/wnl.57.4.621; RA Rogaeva E.A., Fafel K.C., Song Y.Q., Medeiros H., Sato C., Liang Y., RA Richard E., Rogaev E.I., Frommelt P., Sadovnick A.D., Meschino W., RA Rockwood K., Boss M.A., Mayeux R., St George-Hyslop P.; RT "Screening for PS1 mutations in a referral-based series of AD cases: 21 RT novel mutations."; RL Neurology 57:621-625(2001). RN [99] RP VARIANT AD3 SER-266. RX PubMed=11920851; DOI=10.1002/ajmg.10250; RA Matsubara-Tsutsui M., Yasuda M., Yamagata H., Nomura T., Taguchi K., RA Kohara K., Miyoshi K., Miki T.; RT "Molecular evidence of presenilin 1 mutation in familial early onset RT dementia."; RL Am. J. Med. Genet. 114:292-298(2002). RN [100] RP VARIANT AD3 LEU-89. RX PubMed=11796781; DOI=10.1136/jnnp.72.2.266; RA Queralt R., Ezquerra M., Lleo A., Castellvi M., Gelpi J., Ferrer I., RA Acarin N., Pasarin L., Blesa R., Oliva R.; RT "A novel mutation (V89L) in the presenilin 1 gene in a family with early RT onset Alzheimer's disease and marked behavioural disturbances."; RL J. Neurol. Neurosurg. Psych. 72:266-269(2002). RN [101] RP VARIANT AD3 GLY-280. RX PubMed=12370477; DOI=10.1212/wnl.59.7.1108; RA O'Riordan S., McMonagle P., Janssen J.C., Fox N.C., Farrell M., RA Collinge J., Rossor M.N., Hutchinson M.; RT "Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white- RT matter abnormalities."; RL Neurology 59:1108-1110(2002). RN [102] RP VARIANT AD3 PRO-166. RX PubMed=12048239; DOI=10.1073/pnas.112686799; RA Moehlmann T., Winkler E., Xia X., Edbauer D., Murrell J., Capell A., RA Kaether C., Zheng H., Ghetti B., Haass C., Steiner H.; RT "Presenilin-1 mutations of leucine 166 equally affect the generation of the RT Notch and APP intracellular domains independent of their effect on Abeta 42 RT production."; RL Proc. Natl. Acad. Sci. U.S.A. 99:8025-8030(2002). RN [103] RP VARIANT AD3 MET-174. RX PubMed=12484344; DOI=10.1007/s10048-002-0136-6; RA Bertoli-Avella A.M., Marcheco Teruel B., Llibre Rodriguez J.J., RA Gomez Viera N., Borrajero-Martinez I., Severijnen E.A., Joosse M., RA van Duijn C.M., Heredero Baute L., Heutink P.; RT "A novel presenilin 1 mutation (L174 M) in a large Cuban family with early RT onset Alzheimer disease."; RL Neurogenetics 4:97-104(2002). RN [104] RP VARIANT AD3 VAL-271. RX PubMed=12493737; DOI=10.1074/jbc.m211827200; RA Kwok J.B.J., Halliday G.M., Brooks W.S., Dolios G., Laudon H., Murayama O., RA Hallupp M., Badenhop R.F., Vickers J., Wang R., Naslund J., Takashima A., RA Gandy S.E., Schofield P.R.; RT "Presenilin-1 mutation L271V results in altered exon 8 splicing and RT Alzheimer's disease with non-cored plaques and no neuritic dystrophy."; RL J. Biol. Chem. 278:6748-6754(2003). RN [105] RP VARIANTS AD3 CYS-115; ILE-146; VAL-153; CYS-154; ILE-168 DEL; PRO-171; RP ASP-184; PHE-229; VAL-235; LEU-237; VAL-260; PHE-263; HIS-269; MET-377 AND RP VAL-378, AND VARIANT GLY-318. RX PubMed=12552037; DOI=10.1212/01.wnl.0000042088.22694.e3; RA Janssen J.C., Beck J.A., Campbell T.A., Dickinson A., Fox N.C., RA Harvey R.J., Houlden H., Rossor M.N., Collinge J.; RT "Early onset familial Alzheimer's disease: Mutation frequency in 31 RT families."; RL Neurology 60:235-239(2003). RN [106] RP VARIANT PIDB VAL-183, CHARACTERIZATION OF VARIANTS AD3 THR-143 AND VAL-282, RP AND CHARACTERIZATION OF VARIANT PIDB VAL-183. RX PubMed=15122701; DOI=10.1002/ana.20083; RA Dermaut B., Kumar-Singh S., Engelborghs S., Theuns J., Rademakers R., RA Saerens J., Pickut B.A., Peeters K., van den Broeck M., Vennekens K., RA Claes S., Cruts M., Cras P., Martin J.J., Van Broeckhoven C., De Deyn P.P.; RT "A novel presenilin 1 mutation associated with Pick's disease but not beta- RT amyloid plaques."; RL Ann. Neurol. 55:617-626(2004). RN [107] RP VARIANT AD3 PRO-85, AND CHARACTERIZATION OF VARIANT AD3 PRO-85. RX PubMed=15534188; DOI=10.1001/archneur.61.11.1773; RA Ataka S., Tomiyama T., Takuma H., Yamashita T., Shimada H., Tsutada T., RA Kawabata K., Mori H., Miki T.; RT "A novel presenilin-1 mutation (Leu85Pro) in early-onset Alzheimer disease RT with spastic paraparesis."; RL Arch. Neurol. 61:1773-1776(2004). RN [108] RP VARIANT AD3 ILE-278. RX PubMed=15534260; DOI=10.1212/01.wnl.0000143060.98164.1a; RA Godbolt A.K., Beck J.A., Collinge J., Garrard P., Warren J.D., Fox N.C., RA Rossor M.N.; RT "A presenilin 1 R278I mutation presenting with language impairment."; RL Neurology 63:1702-1704(2004). RN [109] RP VARIANT AD3 ASN-154. RX PubMed=15364419; DOI=10.1016/j.neulet.2004.07.057; RA Hattori S., Sakuma K., Wakutani Y., Wada K., Shimoda M., Urakami K., RA Kowa H., Nakashima K.; RT "A novel presenilin 1 mutation (Y154N) in a patient with early onset RT Alzheimer's disease with spastic paraparesis."; RL Neurosci. Lett. 368:319-322(2004). RN [110] RP VARIANT AD3 PHE-170. RX PubMed=16344340; DOI=10.1001/archneur.62.12.1821; RA Snider B.J., Norton J., Coats M.A., Chakraverty S., Hou C.E., Jervis R., RA Lendon C.L., Goate A.M., McKeel D.W. Jr., Morris J.C.; RT "Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy RT bodies in the third decade of life."; RL Arch. Neurol. 62:1821-1830(2005). RN [111] RP VARIANT AD3 LEU-97. RX PubMed=15851849; DOI=10.3233/jad-2005-7204; RA Jia J., Xu E., Shao Y., Jia J., Sun Y., Li D.; RT "One novel presenilin-1 gene mutation in a Chinese pedigree of familial RT Alzheimer's disease."; RL J. Alzheimers Dis. 7:119-124(2005). RN [112] RP VARIANT CMD1U GLY-333. RX PubMed=17186461; DOI=10.1086/509900; RA Li D., Parks S.B., Kushner J.D., Nauman D., Burgess D., Ludwigsen S., RA Partain J., Nixon R.R., Allen C.N., Irwin R.P., Jakobs P.M., Litt M., RA Hershberger R.E.; RT "Mutations of presenilin genes in dilated cardiomyopathy and heart RT failure."; RL Am. J. Hum. Genet. 79:1030-1039(2006). RN [113] RP CHARACTERIZATION OF VARIANTS AD3 VAL-79; THR-143; VAL-231; PHE-262; RP PHE-263; VAL-282 AND ALA-384. RX PubMed=16752394; DOI=10.1002/humu.20336; RA Kumar-Singh S., Theuns J., Van Broeck B., Pirici D., Vennekens K., RA Corsmit E., Cruts M., Dermaut B., Wang R., Van Broeckhoven C.; RT "Mean age-of-onset of familial alzheimer disease caused by presenilin RT mutations correlates with both increased Abeta42 and decreased Abeta40."; RL Hum. Mutat. 27:686-695(2006). RN [114] RP VARIANT AD3 GLU-431. RX PubMed=16628450; DOI=10.1007/s10048-006-0043-3; RA Yescas P., Huertas-Vazquez A., Villarreal-Molina M.T., Rasmussen A., RA Tusie-Luna M.T., Lopez M., Canizales-Quinteros S., Alonso M.E.; RT "Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing RT early-onset Alzheimer's disease in Mexican families."; RL Neurogenetics 7:195-200(2006). RN [115] RP VARIANT AD3 GLU-431. RX PubMed=16897084; DOI=10.1007/s10048-006-0053-1; RA Murrell J., Ghetti B., Cochran E., Macias-Islas M.A., Medina L., RA Varpetian A., Cummings J.L., Mendez M.F., Kawas C., Chui H., Ringman J.M.; RT "The A431E mutation in PSEN1 causing familial Alzheimer's disease RT originating in Jalisco State, Mexico: an additional fifteen families."; RL Neurogenetics 7:277-279(2006). RN [116] RP VARIANT AD3 VAL-79, AND CHARACTERIZATION OF VARIANT AD3 VAL-79. RX PubMed=17366635; DOI=10.1002/ana.21099; RA Kauwe J.S., Jacquart S., Chakraverty S., Wang J., Mayo K., Fagan A.M., RA Holtzman D.M., Morris J.C., Goate A.M.; RT "Extreme cerebrospinal fluid amyloid beta levels identify family with late- RT onset Alzheimer's disease presenilin 1 mutation."; RL Ann. Neurol. 61:446-453(2007). RN [117] RP VARIANT AD3 PHE-170. RX PubMed=17502474; DOI=10.1001/archneur.64.5.738; RA Piccini A., Zanusso G., Borghi R., Noviello C., Monaco S., Russo R., RA Damonte G., Armirotti A., Gelati M., Giordano R., Zambenedetti P., RA Russo C., Ghetti B., Tabaton M.; RT "Association of a presenilin 1 S170F mutation with a novel Alzheimer RT disease molecular phenotype."; RL Arch. Neurol. 64:738-745(2007). RN [118] RP CHARACTERIZATION OF VARIANTS AD3 LEU-117; LEU-146; GLU-246; VAL-260; RP LEU-264 AND GLY-280, FUNCTION, AND MUTAGENESIS OF ASP-257. RX PubMed=17428795; DOI=10.1074/jbc.m611449200; RA Litterst C., Georgakopoulos A., Shioi J., Ghersi E., Wisniewski T., RA Wang R., Ludwig A., Robakis N.K.; RT "Ligand binding and calcium influx induce distinct ectodomain/gamma- RT secretase-processing pathways of EphB2 receptor."; RL J. Biol. Chem. 282:16155-16163(2007). RN [119] RP VARIANT GLY-318. RX PubMed=18485326; DOI=10.1016/j.ajhg.2008.04.014; RA Cornier A.S., Staehling-Hampton K., Delventhal K.M., Saga Y., Caubet J.-F., RA Sasaki N., Ellard S., Young E., Ramirez N., Carlo S.E., Torres J., RA Emans J.B., Turnpenny P.D., Pourquie O.; RT "Mutations in the MESP2 gene cause spondylothoracic dysostosis/Jarcho-Levin RT syndrome."; RL Am. J. Hum. Genet. 82:1334-1341(2008). RN [120] RP CHARACTERIZATION OF VARIANT AD3 THR-213. RX PubMed=18430735; DOI=10.1074/jbc.m801279200; RA Shimojo M., Sahara N., Mizoroki T., Funamoto S., Morishima-Kawashima M., RA Kudo T., Takeda M., Ihara Y., Ichinose H., Takashima A.; RT "Enzymatic characteristics of I213T mutant presenilin-1/gamma-secretase in RT cell models and knock-in mouse brains: familial Alzheimer disease-linked RT mutation impairs gamma-site cleavage of amyloid precursor protein C- RT terminal fragment beta."; RL J. Biol. Chem. 283:16488-16496(2008). RN [121] RP VARIANT AD3 VAL-381. RX PubMed=19797784; DOI=10.1177/1533317509341464; RA Dintchov Traykov L., Mehrabian S., Van den Broeck M., RA Radoslavova Raycheva M., Cruts M., Kirilova Jordanova A., RA Van Broeckhoven C.; RT "Novel PSEN1 mutation in a Bulgarian patient with very early-onset RT Alzheimer's disease, spastic paraparesis, and extrapyramidal signs."; RL Am. J. Alzheimers Dis. Other Demen. 24:404-407(2009). RN [122] RP VARIANT AD3 ARG-217, AND CHARACTERIZATION OF VARIANT AD3 ARG-217. RX PubMed=19667325; DOI=10.1212/wnl.0b013e3181b163ba; RA Norton J.B., Cairns N.J., Chakraverty S., Wang J., Levitch D., Galvin J.E., RA Goate A.; RT "Presenilin1 G217R mutation linked to Alzheimer disease with cotton wool RT plaques."; RL Neurology 73:480-482(2009). RN [123] RP VARIANT AD3 LEU-146. RX PubMed=20164095; DOI=10.1212/wnl.0b013e3181d52785; RA Bruni A.C., Bernardi L., Colao R., Rubino E., Smirne N., Frangipane F., RA Terni B., Curcio S.A., Mirabelli M., Clodomiro A., Di Lorenzo R., RA Maletta R., Anfossi M., Gallo M., Geracitano S., Tomaino C., Muraca M.G., RA Leotta A., Lio S.G., Pinessi L., Rainero I., Sorbi S., Nee L., Milan G., RA Pappata S., Postiglione A., Abbamondi N., Forloni G., St George Hyslop P., RA Rogaeva E., Bugiani O., Giaccone G., Foncin J.F., Spillantini M.G., RA Puccio G.; RT "Worldwide distribution of PSEN1 Met146Leu mutation: a large variability RT for a founder mutation."; RL Neurology 74:798-806(2010). RN [124] RP VARIANT AD3 PHE-435, CHARACTERIZATION OF VARIANTS AD3 PHE-435; GLN-436 AND RP SER-436, MUTAGENESIS OF PRO-433 AND LEU-435, AND FUNCTION. RX PubMed=20460383; DOI=10.1074/jbc.m110.116962; RA Heilig E.A., Xia W., Shen J., Kelleher R.J. III; RT "A presenilin-1 mutation identified in familial Alzheimer disease with RT cotton wool plaques causes a nearly complete loss of gamma-secretase RT activity."; RL J. Biol. Chem. 285:22350-22359(2010). RN [125] RP VARIANT AD3 ASP-206. RX PubMed=21335660; DOI=10.3233/jad-2011-102031; RA Wu Y.Y., Cheng I.H., Lee C.C., Chiu M.J., Lee M.J., Chen T.F., Hsu J.L.; RT "Clinical phenotype of G206D mutation in the presenilin 1 gene in RT pathologically confirmed familial Alzheimer's disease."; RL J. Alzheimers Dis. 25:145-150(2011). RN [126] RP VARIANT CYS-315. RX PubMed=21248752; DOI=10.1038/nature09639; RA Varela I., Tarpey P., Raine K., Huang D., Ong C.K., Stephens P., Davies H., RA Jones D., Lin M.L., Teague J., Bignell G., Butler A., Cho J., RA Dalgliesh G.L., Galappaththige D., Greenman C., Hardy C., Jia M., RA Latimer C., Lau K.W., Marshall J., McLaren S., Menzies A., Mudie L., RA Stebbings L., Largaespada D.A., Wessels L.F.A., Richard S., Kahnoski R.J., RA Anema J., Tuveson D.A., Perez-Mancera P.A., Mustonen V., Fischer A., RA Adams D.J., Rust A., Chan-On W., Subimerb C., Dykema K., Furge K., RA Campbell P.J., Teh B.T., Stratton M.R., Futreal P.A.; RT "Exome sequencing identifies frequent mutation of the SWI/SNF complex gene RT PBRM1 in renal carcinoma."; RL Nature 469:539-542(2011). RN [127] RP VARIANT AD3 ARG-235. RX PubMed=21501661; DOI=10.1016/j.neulet.2011.03.084; RA Antonell A., Balasa M., Oliva R., Llado A., Bosch B., Fabregat N., RA Fortea J., Molinuevo J.L., Sanchez-Valle R.; RT "A novel PSEN1 gene mutation (L235R) associated with familial early-onset RT Alzheimer's disease."; RL Neurosci. Lett. 496:40-42(2011). RN [128] RP CHARACTERIZATION OF VARIANTS AD3 LEU-146; ARG-163 AND ALA-280. RX PubMed=22461631; DOI=10.1074/jbc.m111.300483; RA Chau D.M., Crump C.J., Villa J.C., Scheinberg D.A., Li Y.M.; RT "Familial Alzheimer disease presenilin-1 mutations alter the active site RT conformation of gamma-secretase."; RL J. Biol. Chem. 287:17288-17296(2012). RN [129] RP VARIANTS AD3 ARG-134; ARG-163 AND VAL-262, AND VARIANT TYR-214. RX PubMed=22503161; DOI=10.1016/j.neurobiolaging.2012.02.020; RA Lohmann E., Guerreiro R.J., Erginel-Unaltuna N., Gurunlian N., Bilgic B., RA Gurvit H., Hanagasi H.A., Luu N., Emre M., Singleton A.; RT "Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish RT dementia patients."; RL Neurobiol. Aging 33:1850.E17-1850.E27(2012). RN [130] RP VARIANT AD3 PHE-159. RX PubMed=23123781; DOI=10.1016/j.neulet.2012.10.037; RA Kerchner G.A., Holbrook K.; RT "Novel presenilin-1 Y159F sequence variant associated with early-onset RT Alzheimer's disease."; RL Neurosci. Lett. 531:142-144(2012). RN [131] RP CHARACTERIZATION OF VARIANTS AD3 PRO-166 AND GLN-436, AND MUTAGENESIS OF RP ASP-257 AND ASP-385. RX PubMed=22529981; DOI=10.1371/journal.pone.0035133; RA Cacquevel M., Aeschbach L., Houacine J., Fraering P.C.; RT "Alzheimer's disease-linked mutations in presenilin-1 result in a drastic RT loss of activity in purified gamma-secretase complexes."; RL PLoS ONE 7:E35133-E35133(2012). RN [132] RP CHARACTERIZATION OF VARIANTS AD3 PRO-166; ILE-278; ALA-384; VAL-392; RP TYR-410 AND PHE-435. RX PubMed=23843529; DOI=10.1523/jneurosci.0954-13.2013; RA Heilig E.A., Gutti U., Tai T., Shen J., Kelleher R.J. III; RT "Trans-dominant negative effects of pathogenic PSEN1 mutations on gamma- RT secretase activity and Abeta production."; RL J. Neurosci. 33:11606-11617(2013). RN [133] RP VARIANT AD3 PHE-381. RX PubMed=24121961; DOI=10.3233/jad-131340; RA Dolzhanskaya N., Gonzalez M.A., Sperziani F., Stefl S., Messing J., RA Wen G.Y., Alexov E., Zuchner S., Velinov M.; RT "A novel p.Leu(381)Phe mutation in presenilin 1 is associated with very RT early onset and unusually fast progressing dementia as well as lysosomal RT inclusions typically seen in Kufs disease."; RL J. Alzheimers Dis. 39:23-27(2014). RN [134] RP VARIANT AD3 VAL-153. RX PubMed=24495933; DOI=10.1016/j.neulet.2014.01.016; RA Cornejo-Olivas M.R., Yu C.E., Mazzetti P., Mata I.F., Meza M., RA Lindo-Samanamud S., Leverenz J.B., Bird T.D.; RT "Clinical and molecular studies reveal a PSEN1 mutation (L153V) in a RT Peruvian family with early-onset Alzheimer's disease."; RL Neurosci. Lett. 563:140-143(2014). RN [135] RP VARIANT AD3 VAL-275. RX PubMed=24582897; DOI=10.1016/j.neulet.2014.02.034; RA Luedecke D., Becktepe J.S., Lehmbeck J.T., Finckh U., Yamamoto R., Jahn H., RA Boelmans K.; RT "A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial RT Alzheimer disease."; RL Neurosci. Lett. 566:115-119(2014). RN [136] RP VARIANT AD3 THR-83. RX PubMed=26145164; DOI=10.1016/j.neurobiolaging.2015.06.007; RA Achouri-Rassas A., Ben Ali N., Fray S., Hadj Fredj S., Kechaou M., RA Zakraoui N.O., Cherif A., Chabbi S., Anane N., Messaoud T., Gouider R., RA Belal S.; RT "Novel presenilin 1 mutation (p.I83T) in Tunisian family with early-onset RT Alzheimer's disease."; RL Neurobiol. Aging 36:2904.E09-2904.E11(2015). RN [137] RP VARIANTS AD3 ALA-206 AND VAL-378. RX PubMed=27073747; RA Ravenscroft T.A., Pottier C., Murray M.E., Baker M., Christopher E., RA Levitch D., Brown P.H., Barker W., Duara R., Greig-Custo M., Betancourt A., RA English M., Sun X., Ertekin-Taner N., Graff-Radford N.R., Dickson D.W., RA Rademakers R.; RT "The presenilin 1 p.Gly206Ala mutation is a frequent cause of early-onset RT Alzheimer's disease in Hispanics in Florida."; RL Am. J. Neurodegener. Dis. 5:94-101(2016). RN [138] RP VARIANT AD3 THR-408. RX PubMed=26549787; DOI=10.1016/j.neulet.2015.11.004; RA Tedde A., Bartoli A., Piaceri I., Ferrara S., Bagnoli S., Serio A., RA Sorbi S., Nacmias B.; RT "Novel presenilin 1 mutation (Ile408Thr) in an Italian family with late- RT onset Alzheimer's disease."; RL Neurosci. Lett. 610:150-153(2016). RN [139] RP VARIANT ARG-311, CHARACTERIZATION OF VARIANTS ALA-280 AND ARG-311, AND RP FUNCTION. RX PubMed=28269784; DOI=10.3233/jad-161188; RA Dong J., Qin W., Wei C., Tang Y., Wang Q., Jia J.; RT "A novel PSEN1 K311R mutation discovered in Chinese families with late- RT onset Alzheimer's disease affects amyloid-beta production and tau RT phosphorylation."; RL J. Alzheimers Dis. 57:613-623(2017). RN [140] RP CHARACTERIZATION OF VARIANTS AD3 GLN-35; VAL-79; LEU-82; PRO-85; LEU-89; RP SER-92; MET-94; PHE-96; LEU-97; HIS-115; ASN-116; ASP-120; LYS-120; RP ARG-134; ASP-135; VAL-139; THR-143; LEU-146; ILE-147; VAL-153; ASN-154; RP ARG-163; TYR-163; PRO-166; PRO-169; PHE-170; PRO-171; TRP-173; MET-174; RP LEU-177; PRO-178; VAL-183; ASP-184; ALA-206; SER-206; ARG-209; VAL-209; RP LEU-213; ARG-217; ARG-222; PHE-229; THR-231; LEU-233; THR-233; ARG-235; RP PRO-235; VAL-235; ILE-237; GLU-246; SER-250; VAL-260; PHE-261; PHE-262; RP ARG-263; LEU-264; SER-266; SER-267; GLY-269; VAL-271; ARG-274; VAL-275; RP ALA-280; GLY-280; ARG-282; VAL-285; VAL-286; ILE-354; GLN-358; GLU-378; RP VAL-378; VAL-381; ALA-384; ILE-390; VAL-392; VAL-394; THR-396; SER-405; RP THR-409; TYR-410; PHE-418; PRO-426; GLU-431; PHE-435; SER-436 AND VAL-439, RP CHARACTERIZATION OF VARIANT CMD1U GLY-333, AND MUTAGENESIS OF THR-99; RP PHE-105; ARG-108; LEU-113; PRO-117; GLU-123; HIS-131; ALA-136; ILE-143; RP LEU-150; TRP-165; ILE-168; PHE-176; GLU-184; ILE-202; SER-212; HIS-214; RP LEU-219; GLN-223; LEU-226; SER-230; ILE-238; LYS-239; THR-245; LEU-248; RP TYR-256; VAL-272; GLU-273; ARG-278; PRO-284; THR-291; ARG-352; SER-365; RP ARG-377; PHE-386; VAL-391; VAL-412; LEU-420; LEU-424; ALA-434 AND ILE-437. RX PubMed=27930341; DOI=10.1073/pnas.1618657114; RA Sun L., Zhou R., Yang G., Shi Y.; RT "Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro RT production of Abeta42 and Abeta40 peptides by gamma-secretase."; RL Proc. Natl. Acad. Sci. U.S.A. 114:E476-E485(2017). RN [141] RP VARIANT AD3 ILE-116. RX PubMed=30200536; DOI=10.3390/ijms19092604; RA Bagyinszky E., Lee H.M., Van Giau V., Koh S.B., Jeong J.H., An S.S.A., RA Kim S.; RT "PSEN1 p.Thr116Ile variant in two Korean families with young onset RT Alzheimer's disease."; RL Int. J. Mol. Sci. 19:0-0(2018). RN [142] RP VARIANT AD3 ASN-116. RX PubMed=29404783; DOI=10.1007/s00702-018-1850-z; RA Sutovsky S., Smolek T., Turcani P., Petrovic R., Brandoburova P., RA Jadhav S., Novak P., Attems J., Zilka N.; RT "Neuropathology and biochemistry of early onset familial Alzheimer's RT disease caused by presenilin-1 missense mutation Thr116Asn."; RL J. Neural Transm. 125:965-976(2018). RN [143] RP VARIANTS AD3 PHE-142 AND ASP-206. RX PubMed=29175279; DOI=10.1016/j.neurobiolaging.2017.10.011; RA Wang J.C., Alinaghi S., Tafakhori A., Sikora E., Azcona L.J., RA Karkheiran S., Goate A., Paisan-Ruiz C., Darvish H.; RT "Genetic screening in two Iranian families with early-onset Alzheimer's RT disease identified a novel PSEN1 mutation."; RL Neurobiol. Aging 62:E15-E17(2018). RN [144] RP VARIANT AD3 ALA-417. RX PubMed=30180983; DOI=10.1016/j.neurobiolaging.2018.08.003; RA Giau V.V., Wang M.J., Bagyinszky E., Youn Y.C., An S.S.A., Kim S.; RT "Novel PSEN1 p.Gly417Ala mutation in a Korean patient with early-onset RT Alzheimer's disease with parkinsonism."; RL Neurobiol. Aging 72:E13-E17(2018). RN [145] RP VARIANT AD3 PHE-170. RX PubMed=29466804; DOI=10.1159/000485899; RA Tiedt H.O., Benjamin B., Niedeggen M., Lueschow A.; RT "Phenotypic variability in autosomal dominant familial Alzheimer disease RT due to the S170F mutation of presenilin-1."; RL Neurodegener. Dis. 18:57-68(2018). CC -!- FUNCTION: Catalytic subunit of the gamma-secretase complex, an CC endoprotease complex that catalyzes the intramembrane cleavage of CC integral membrane proteins such as Notch receptors and APP (amyloid- CC beta precursor protein) (PubMed:10206644, PubMed:10545183, CC PubMed:10593990, PubMed:10811883, PubMed:10899933, PubMed:12679784, CC PubMed:12740439, PubMed:15274632, PubMed:20460383, PubMed:25043039, CC PubMed:26280335, PubMed:28269784, PubMed:30598546, PubMed:30630874). CC Requires the presence of the other members of the gamma-secretase CC complex for protease activity (PubMed:15274632, PubMed:25043039, CC PubMed:26280335, PubMed:30598546, PubMed:30630874). Plays a role in CC Notch and Wnt signaling cascades and regulation of downstream processes CC via its role in processing key regulatory proteins, and by regulating CC cytosolic CTNNB1 levels (PubMed:10593990, PubMed:10811883, CC PubMed:10899933, PubMed:9738936). Stimulates cell-cell adhesion via its CC interaction with CDH1; this stabilizes the complexes between CDH1 (E- CC cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 CC and JUP (gamma-catenin) (PubMed:11953314). Under conditions of CC apoptosis or calcium influx, cleaves CDH1 (PubMed:11953314). This CC promotes the disassembly of the complexes between CDH1 and CTNND1, JUP CC and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby CC negatively regulates Wnt signaling (PubMed:11953314, PubMed:9738936). CC Required for normal embryonic brain and skeleton development, and for CC normal angiogenesis (By similarity). Mediates the proteolytic cleavage CC of EphB2/CTF1 into EphB2/CTF2 (PubMed:17428795, PubMed:28269784). The CC holoprotein functions as a calcium-leak channel that allows the passive CC movement of calcium from endoplasmic reticulum to cytosol and is CC therefore involved in calcium homeostasis (PubMed:16959576, CC PubMed:25394380). Involved in the regulation of neurite outgrowth CC (PubMed:15004326, PubMed:20460383). Is a regulator of presynaptic CC facilitation, spike transmission and synaptic vesicles replenishment in CC a process that depends on gamma-secretase activity. It acts through the CC control of SYT7 presynaptic expression (By similarity). CC {ECO:0000250|UniProtKB:P49769, ECO:0000269|PubMed:10206644, CC ECO:0000269|PubMed:10545183, ECO:0000269|PubMed:10593990, CC ECO:0000269|PubMed:10811883, ECO:0000269|PubMed:10899933, CC ECO:0000269|PubMed:11953314, ECO:0000269|PubMed:12679784, CC ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:15004326, CC ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:15341515, CC ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:16959576, CC ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:20460383, CC ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25394380, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:28269784, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, CC ECO:0000269|PubMed:9738936}. CC -!- SUBUNIT: Homodimer. The functional gamma-secretase complex is composed CC of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), CC nicastrin (NCSTN), APH1 (APH1A/APH1B) and PEN2 (PubMed:12679784, CC PubMed:12740439, PubMed:15274632, PubMed:25043039, PubMed:25394380, CC PubMed:26280335, PubMed:30598546, PubMed:30630874). Such minimal CC complex is sufficient for secretase activity (PubMed:12679784, CC PubMed:12740439, PubMed:15274632, PubMed:25043039, PubMed:26280335, CC PubMed:30598546, PubMed:30630874). Other components which are CC associated with the complex include SLC25A64, SLC5A7, PHB and PSEN1 CC isoform 3. As part of the gamma-secretase complex, interacts with CRB2 CC (via transmembrane domain) (PubMed:20299451). Predominantly heterodimer CC of a N-terminal (NTF) and a C-terminal (CTF) endoproteolytical fragment CC (PubMed:15274632). Associates with proteolytic processed C-terminal CC fragments C83 and C99 of the amyloid precursor protein (APP) (via CC transmembrane domain) (PubMed:30630874). Associates with NOTCH1 (via CC transmembrane domain) (PubMed:10593990, PubMed:30598546). Associates CC with cadherin/catenin adhesion complexes through direct binding to CDH1 CC or CDH2 (PubMed:11953314, PubMed:14515347, PubMed:16126725). CC Interaction with CDH1 stabilizes the complex and stimulates cell-cell CC aggregation (PubMed:11953314). Interaction with CDH2 is essential for CC trafficking of CDH2 from the endoplasmic reticulum to the plasma CC membrane (PubMed:14515347). Interacts with CTNND2, CTNNB1, CTNND1, JUP, CC HERPUD1, FLNA, FLNB, MTCH1, PKP4 and PARL (PubMed:10037471, CC PubMed:10551805, PubMed:11799129, PubMed:11953314, PubMed:12214059, CC PubMed:16126725, PubMed:9437013, PubMed:9738936). Interacts through its CC N-terminus with GFAP (isoform 2) (PubMed:12058025). Interacts with CC DOCK3; this interaction mediates the membrane association of DOCK3 CC (PubMed:10854253). Interacts with isoform 1 and isoform 3 of UBQLN1 CC (PubMed:21143716). {ECO:0000250|UniProtKB:P49769, CC ECO:0000269|PubMed:10037471, ECO:0000269|PubMed:10551805, CC ECO:0000269|PubMed:10854253, ECO:0000269|PubMed:11799129, CC ECO:0000269|PubMed:11953314, ECO:0000269|PubMed:12058025, CC ECO:0000269|PubMed:12214059, ECO:0000269|PubMed:12679784, CC ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:14515347, CC ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:16126725, CC ECO:0000269|PubMed:20299451, ECO:0000269|PubMed:21143716, CC ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25394380, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:30598546, CC ECO:0000269|PubMed:30630874, ECO:0000269|PubMed:9437013, CC ECO:0000269|PubMed:9738936}. CC -!- INTERACTION: CC P49768; Q02410: APBA1; NbExp=4; IntAct=EBI-297277, EBI-368690; CC P49768; Q96BI3: APH1A; NbExp=3; IntAct=EBI-297277, EBI-2606935; CC P49768; P05067: APP; NbExp=6; IntAct=EBI-297277, EBI-77613; CC P49768; P05067-4: APP; NbExp=4; IntAct=EBI-297277, EBI-302641; CC P49768; P56817: BACE1; NbExp=6; IntAct=EBI-297277, EBI-2433139; CC P49768; Q16543: CDC37; NbExp=3; IntAct=EBI-297277, EBI-295634; CC P49768; P12830: CDH1; NbExp=2; IntAct=EBI-297277, EBI-727477; CC P49768; Q9BQ95: ECSIT; NbExp=4; IntAct=EBI-297277, EBI-712452; CC P49768; P21333: FLNA; NbExp=2; IntAct=EBI-297277, EBI-350432; CC P49768; O75369: FLNB; NbExp=2; IntAct=EBI-297277, EBI-352089; CC P49768; Q92542: NCSTN; NbExp=6; IntAct=EBI-297277, EBI-998440; CC P49768; Q99569: PKP4; NbExp=3; IntAct=EBI-297277, EBI-726447; CC P49768; Q9NZ42: PSENEN; NbExp=4; IntAct=EBI-297277, EBI-998468; CC P49768; P50502: ST13; NbExp=3; IntAct=EBI-297277, EBI-357285; CC P49768; P55061: TMBIM6; NbExp=12; IntAct=EBI-297277, EBI-1045825; CC P49768; P49755: TMED10; NbExp=4; IntAct=EBI-297277, EBI-998422; CC P49768; Q9NZC2: TREM2; NbExp=5; IntAct=EBI-297277, EBI-14036387; CC P49768; Q9UMX0: UBQLN1; NbExp=3; IntAct=EBI-297277, EBI-741480; CC P49768; O35430: Apba1; Xeno; NbExp=2; IntAct=EBI-297277, EBI-704760; CC P49768; P98084: Apba2; Xeno; NbExp=2; IntAct=EBI-297277, EBI-81669; CC P49768; P62493: RAB11A; Xeno; NbExp=2; IntAct=EBI-297277, EBI-7030357; CC P49768-2; P63010-2: AP2B1; NbExp=6; IntAct=EBI-11047108, EBI-11529439; CC P49768-2; P05067: APP; NbExp=6; IntAct=EBI-11047108, EBI-77613; CC P49768-2; P16870: CPE; NbExp=3; IntAct=EBI-11047108, EBI-711320; CC P49768-2; Q5D0E6-2: DALRD3; NbExp=3; IntAct=EBI-11047108, EBI-9090939; CC P49768-2; Q9H816: DCLRE1B; NbExp=3; IntAct=EBI-11047108, EBI-3508943; CC P49768-2; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-11047108, EBI-396453; CC P49768-2; Q06787-7: FMR1; NbExp=3; IntAct=EBI-11047108, EBI-25856644; CC P49768-2; P02792: FTL; NbExp=3; IntAct=EBI-11047108, EBI-713279; CC P49768-2; P68431: H3C12; NbExp=6; IntAct=EBI-11047108, EBI-79722; CC P49768-2; Q12891: HYAL2; NbExp=3; IntAct=EBI-11047108, EBI-2806068; CC P49768-2; Q6DN90-2: IQSEC1; NbExp=6; IntAct=EBI-11047108, EBI-21911304; CC P49768-2; Q9NVX7-2: KBTBD4; NbExp=3; IntAct=EBI-11047108, EBI-25871195; CC P49768-2; Q9BYQ4: KRTAP9-2; NbExp=3; IntAct=EBI-11047108, EBI-1044640; CC P49768-2; Q9BYZ2: LDHAL6B; NbExp=6; IntAct=EBI-11047108, EBI-1108377; CC P49768-2; Q8TDB4: MGARP; NbExp=6; IntAct=EBI-11047108, EBI-4397720; CC P49768-2; A4FUJ8: MKL1; NbExp=6; IntAct=EBI-11047108, EBI-21250407; CC P49768-2; Q9Y605: MRFAP1; NbExp=3; IntAct=EBI-11047108, EBI-995714; CC P49768-2; Q86WS3: OOSP2; NbExp=3; IntAct=EBI-11047108, EBI-25888682; CC P49768-2; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-11047108, EBI-1058491; CC P49768-2; Q13113: PDZK1IP1; NbExp=6; IntAct=EBI-11047108, EBI-716063; CC P49768-2; P53350: PLK1; NbExp=3; IntAct=EBI-11047108, EBI-476768; CC P49768-2; O14494: PLPP1; NbExp=3; IntAct=EBI-11047108, EBI-2865290; CC P49768-2; Q9NZ42: PSENEN; NbExp=3; IntAct=EBI-11047108, EBI-998468; CC P49768-2; Q6ZNA4-2: RNF111; NbExp=6; IntAct=EBI-11047108, EBI-21535400; CC P49768-2; Q9ULX5: RNF112; NbExp=6; IntAct=EBI-11047108, EBI-25829984; CC P49768-2; Q8N488: RYBP; NbExp=6; IntAct=EBI-11047108, EBI-752324; CC P49768-2; Q2NKQ1-4: SGSM1; NbExp=3; IntAct=EBI-11047108, EBI-10182463; CC P49768-2; Q9GZS3: SKIC8; NbExp=6; IntAct=EBI-11047108, EBI-358545; CC P49768-2; Q3KNW5: SLC10A6; NbExp=3; IntAct=EBI-11047108, EBI-18159983; CC P49768-2; Q99932-2: SPAG8; NbExp=6; IntAct=EBI-11047108, EBI-11959123; CC P49768-2; O00300: TNFRSF11B; NbExp=3; IntAct=EBI-11047108, EBI-15481185; CC P49768-2; Q96NC0: ZMAT2; NbExp=6; IntAct=EBI-11047108, EBI-2682299; CC PRO_0000025591; Q63053: Arc; Xeno; NbExp=3; IntAct=EBI-2606326, EBI-5275794; CC PRO_0000025592; P35613: BSG; NbExp=6; IntAct=EBI-2606356, EBI-750709; CC PRO_0000025592; Q92542: NCSTN; NbExp=2; IntAct=EBI-2606356, EBI-998440; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum CC {ECO:0000269|PubMed:25394380}. Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:8574969, CC ECO:0000269|PubMed:9738936, ECO:0000305|PubMed:10037471, CC ECO:0000305|PubMed:15274632}; Multi-pass membrane protein CC {ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25918421, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26623517, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Golgi CC apparatus membrane {ECO:0000269|PubMed:10593990, CC ECO:0000269|PubMed:8574969, ECO:0000305|PubMed:10037471, CC ECO:0000305|PubMed:15274632}; Multi-pass membrane protein CC {ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25918421, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26623517, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Cytoplasmic CC granule {ECO:0000269|PubMed:11987239}. Cell membrane CC {ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:11953314, CC ECO:0000269|PubMed:11987239, ECO:0000269|PubMed:21143716}; Multi-pass CC membrane protein {ECO:0000269|PubMed:25918421, CC ECO:0000269|PubMed:26623517, ECO:0000269|PubMed:30598546, CC ECO:0000269|PubMed:30630874}. Cell projection, growth cone CC {ECO:0000269|PubMed:15004326}. Early endosome CC {ECO:0000269|PubMed:25394380}. Early endosome membrane CC {ECO:0000305|PubMed:25394380}; Multi-pass membrane protein CC {ECO:0000269|PubMed:25918421, ECO:0000269|PubMed:26623517, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Cell CC projection, neuron projection {ECO:0000269|PubMed:15004326}. Cell CC projection, axon {ECO:0000250|UniProtKB:Q4JIM4}. Synapse CC {ECO:0000250|UniProtKB:Q4JIM4}. Note=Translocates with bound NOTCH1 CC from the endoplasmic reticulum and/or Golgi to the cell surface CC (PubMed:10593990). Colocalizes with CDH1/2 at sites of cell-cell CC contact. Colocalizes with CTNNB1 in the endoplasmic reticulum and the CC proximity of the plasma membrane (PubMed:9738936). Also present in CC azurophil granules of neutrophils (PubMed:11987239). Colocalizes with CC UBQLN1 in the cell membrane and in cytoplasmic juxtanuclear structures CC called aggresomes (PubMed:21143716). Also highly enriched in CC mitochondria-associated endoplasmic reticulum membrane contact site (By CC similarity). {ECO:0000250|UniProtKB:P49769, CC ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:11987239, CC ECO:0000269|PubMed:21143716, ECO:0000269|PubMed:9738936}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=7; CC Name=1; Synonyms=I-467; CC IsoId=P49768-1; Sequence=Displayed; CC Name=2; Synonyms=I-463; CC IsoId=P49768-2; Sequence=VSP_005191; CC Name=3; Synonyms=I-374; CC IsoId=P49768-3; Sequence=VSP_005191, VSP_005192; CC Name=4; Synonyms=Minilin; CC IsoId=P49768-4; Sequence=VSP_007986, VSP_007987; CC Name=5; CC IsoId=P49768-5; Sequence=VSP_005192; CC Name=6; CC IsoId=P49768-6; Sequence=VSP_012288; CC Name=7; CC IsoId=P49768-7; Sequence=VSP_041440; CC -!- TISSUE SPECIFICITY: Detected in azurophile granules in neutrophils and CC in platelet cytoplasmic granules (at protein level) (PubMed:11987239). CC Expressed in a wide range of tissues including various regions of the CC brain, liver, spleen and lymph nodes (PubMed:7596406, PubMed:8574969, CC PubMed:8641442). {ECO:0000269|PubMed:11987239, CC ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:8574969, CC ECO:0000269|PubMed:8641442}. CC -!- DOMAIN: The PAL motif is required for normal active site conformation. CC {ECO:0000269|PubMed:16305624}. CC -!- DOMAIN: Substrates, such as NOTCH1 and APP peptides, are bound between CC PSEN1 transmembrane domains and via the first lumenal loop and the CC cytoplasmic loop between the sixth and seventh transmembrane domains. CC Substrate binding causes a conformation change and formation of an CC intermolecular antiparallel beta-sheet between PSEN1 and its CC substrates. {ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. CC -!- PTM: Heterogeneous proteolytic processing generates N-terminal (NTF) CC and C-terminal (CTF) fragments of approximately 35 and 20 kDa, CC respectively. During apoptosis, the C-terminal fragment (CTF) is CC further cleaved by caspase-3 to produce the fragment, PS1-CTF12. CC {ECO:0000269|PubMed:10545183, ECO:0000269|PubMed:15274632, CC ECO:0000269|PubMed:9173929, ECO:0000269|PubMed:9485372}. CC -!- PTM: After endoproteolysis, the C-terminal fragment (CTF) is CC phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on CC Ser-346 inhibits endoproteolysis. {ECO:0000269|PubMed:14576165, CC ECO:0000269|PubMed:9144240}. CC -!- DISEASE: Alzheimer disease 3 (AD3) [MIM:607822]: A familial early-onset CC form of Alzheimer disease. Alzheimer disease is a neurodegenerative CC disorder characterized by progressive dementia, loss of cognitive CC 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:10025789, ECO:0000269|PubMed:10090481, CC ECO:0000269|PubMed:10200054, ECO:0000269|PubMed:10208579, CC ECO:0000269|PubMed:10439444, ECO:0000269|PubMed:10441572, CC ECO:0000269|PubMed:10447269, ECO:0000269|PubMed:10533070, CC ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10644793, CC ECO:0000269|PubMed:11027672, ECO:0000269|PubMed:11524469, CC ECO:0000269|PubMed:11561050, ECO:0000269|PubMed:11568920, CC ECO:0000269|PubMed:11701593, ECO:0000269|PubMed:11710891, CC ECO:0000269|PubMed:11796781, ECO:0000269|PubMed:11920851, CC ECO:0000269|PubMed:12048239, ECO:0000269|PubMed:12058025, CC ECO:0000269|PubMed:12370477, ECO:0000269|PubMed:12484344, CC ECO:0000269|PubMed:12493737, ECO:0000269|PubMed:12552037, CC ECO:0000269|PubMed:15004326, ECO:0000269|PubMed:15122701, CC ECO:0000269|PubMed:15364419, ECO:0000269|PubMed:15534188, CC ECO:0000269|PubMed:15534260, ECO:0000269|PubMed:15851849, CC ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:16344340, CC ECO:0000269|PubMed:16628450, ECO:0000269|PubMed:16752394, CC ECO:0000269|PubMed:16897084, ECO:0000269|PubMed:16959576, CC ECO:0000269|PubMed:17366635, ECO:0000269|PubMed:17428795, CC ECO:0000269|PubMed:17502474, ECO:0000269|PubMed:18430735, CC ECO:0000269|PubMed:19667325, ECO:0000269|PubMed:19797784, CC ECO:0000269|PubMed:20164095, ECO:0000269|PubMed:20460383, CC ECO:0000269|PubMed:21335660, ECO:0000269|PubMed:21501661, CC ECO:0000269|PubMed:22461631, ECO:0000269|PubMed:22503161, CC ECO:0000269|PubMed:22529981, ECO:0000269|PubMed:23123781, CC ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:24121961, CC ECO:0000269|PubMed:24495933, ECO:0000269|PubMed:24582897, CC ECO:0000269|PubMed:25394380, ECO:0000269|PubMed:26145164, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26549787, CC ECO:0000269|PubMed:27073747, ECO:0000269|PubMed:27930341, CC ECO:0000269|PubMed:29175279, ECO:0000269|PubMed:29404783, CC ECO:0000269|PubMed:29466804, ECO:0000269|PubMed:30180983, CC ECO:0000269|PubMed:30200536, ECO:0000269|PubMed:7550356, CC ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:7651536, CC ECO:0000269|PubMed:8634711, ECO:0000269|PubMed:8634712, CC ECO:0000269|PubMed:8733303, ECO:0000269|PubMed:8837617, CC ECO:0000269|PubMed:8875251, ECO:0000269|PubMed:9172170, CC ECO:0000269|PubMed:9225696, ECO:0000269|PubMed:9298817, CC ECO:0000269|PubMed:9384602, ECO:0000269|PubMed:9507958, CC ECO:0000269|PubMed:9521423, ECO:0000269|PubMed:9719376, CC ECO:0000269|PubMed:9831473, ECO:0000269|PubMed:9833068, CC ECO:0000269|Ref.95}. Note=The disease is caused by variants affecting CC the gene represented in this entry. CC -!- DISEASE: Frontotemporal dementia 1 (FTD1) [MIM:600274]: A form of CC dementia characterized by pathologic finding of frontotemporal lobar CC degeneration, presenile dementia with behavioral changes, deterioration CC of cognitive capacities and loss of memory. In some cases, parkinsonian CC symptoms are prominent. Neuropathological changes include CC frontotemporal atrophy often associated with atrophy of the basal CC ganglia, substantia nigra, amygdala. In most cases, protein tau CC deposits are found in glial cells and/or neurons. CC {ECO:0000269|PubMed:11094121}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Cardiomyopathy, dilated, 1U (CMD1U) [MIM:613694]: A disorder CC characterized by ventricular dilation and impaired systolic function, CC resulting in congestive heart failure and arrhythmia. Patients are at CC risk of premature death. {ECO:0000269|PubMed:17186461, CC ECO:0000269|PubMed:27930341}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Acne inversa, familial, 3 (ACNINV3) [MIM:613737]: A chronic CC relapsing inflammatory disease of the hair follicles characterized by CC recurrent draining sinuses, painful skin abscesses, and disfiguring CC scars. Manifestations typically appear after puberty. CC {ECO:0000269|PubMed:20929727}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Pick disease of the brain (PIDB) [MIM:172700]: A rare form of CC dementia pathologically defined by severe atrophy, neuronal loss and CC gliosis. It is characterized by the occurrence of tau-positive CC inclusions, swollen neurons (Pick cells) and argentophilic neuronal CC inclusions known as Pick bodies that disproportionally affect the CC frontal and temporal cortical regions. Clinical features include CC aphasia, apraxia, confusion, anomia, memory loss and personality CC deterioration. {ECO:0000269|PubMed:15122701}. Note=The gene represented CC in this entry may be involved in disease pathogenesis. CC -!- MISCELLANEOUS: [Isoform 3]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 5]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the peptidase A22A family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Alzheimer Research Forum; Note=Presenilins CC mutations; CC URL="https://www.alzforum.org/mutations/psen-1"; 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; L42110; AAB46416.1; -; mRNA. DR EMBL; L76517; AAB46370.1; -; mRNA. DR EMBL; L76528; AAB46371.1; -; Genomic_DNA. DR EMBL; L76519; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76520; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76521; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76522; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76523; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76524; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76525; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76526; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76527; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; U40379; AAB05894.1; -; mRNA. DR EMBL; U40380; AAB05895.1; -; mRNA. DR EMBL; AJ008005; CAA07825.1; -; mRNA. DR EMBL; AF109907; AAC97960.1; -; Genomic_DNA. DR EMBL; AF416717; AAL16811.1; -; mRNA. DR EMBL; AK312531; BAG35430.1; -; mRNA. DR EMBL; AC004858; AAF19253.1; -; Genomic_DNA. DR EMBL; AC004858; AAF19254.1; -; Genomic_DNA. DR EMBL; CH471061; EAW81092.1; -; Genomic_DNA. DR EMBL; BC011729; AAH11729.1; -; mRNA. DR EMBL; D84149; BAA20883.1; -; Genomic_DNA. DR CCDS; CCDS9812.1; -. [P49768-1] DR CCDS; CCDS9813.1; -. [P49768-2] DR PIR; S58396; S58396. DR PIR; S63683; S63683. DR PIR; S63684; S63684. DR RefSeq; NP_000012.1; NM_000021.4. [P49768-1] DR RefSeq; NP_015557.2; NM_007318.3. [P49768-2] DR RefSeq; XP_005267921.1; XM_005267864.4. [P49768-1] DR RefSeq; XP_005267923.1; XM_005267866.3. [P49768-2] DR RefSeq; XP_011535274.1; XM_011536972.3. [P49768-1] DR RefSeq; XP_011535275.1; XM_011536973.3. [P49768-2] DR RefSeq; XP_011535276.1; XM_011536974.3. [P49768-2] DR RefSeq; XP_047287556.1; XM_047431600.1. [P49768-1] DR RefSeq; XP_047287557.1; XM_047431601.1. [P49768-1] DR RefSeq; XP_047287558.1; XM_047431602.1. [P49768-2] DR RefSeq; XP_054232388.1; XM_054376413.1. [P49768-1] DR RefSeq; XP_054232389.1; XM_054376414.1. [P49768-1] DR RefSeq; XP_054232390.1; XM_054376415.1. [P49768-1] DR RefSeq; XP_054232391.1; XM_054376416.1. [P49768-1] DR RefSeq; XP_054232392.1; XM_054376417.1. [P49768-2] DR RefSeq; XP_054232393.1; XM_054376418.1. [P49768-2] DR RefSeq; XP_054232394.1; XM_054376419.1. [P49768-2] DR RefSeq; XP_054232395.1; XM_054376420.1. [P49768-2] DR PDB; 2KR6; NMR; -; A=292-467. DR PDB; 4UIS; EM; 4.40 A; B=81-463. DR PDB; 5A63; EM; 3.40 A; B=1-467. DR PDB; 5FN2; EM; 4.20 A; B=1-467. DR PDB; 5FN3; EM; 4.10 A; B=1-467. DR PDB; 5FN4; EM; 4.00 A; B=1-467. DR PDB; 5FN5; EM; 4.30 A; B=1-467. DR PDB; 6IDF; EM; 2.70 A; B=1-467. DR PDB; 6IYC; EM; 2.60 A; B=1-467. DR PDB; 6LQG; EM; 3.10 A; B=1-467. DR PDB; 6LR4; EM; 3.00 A; B=1-467. DR PDB; 7C9I; EM; 3.10 A; B=1-467. DR PDB; 7D8X; EM; 2.60 A; B=1-467. DR PDB; 7Y5T; EM; 2.90 A; B=1-467. DR PDB; 8IM7; EM; 3.40 A; B=1-467. DR PDB; 8K8E; EM; 2.60 A; B=1-467. DR PDB; 8KCO; EM; 2.80 A; B=1-467. DR PDB; 8KCP; EM; 3.00 A; B=1-467. DR PDB; 8KCS; EM; 2.40 A; B=1-467. DR PDB; 8KCT; EM; 2.60 A; B=1-467. DR PDB; 8KCU; EM; 2.70 A; B=1-467. DR PDB; 8OQY; EM; 3.30 A; B=1-467. DR PDB; 8OQZ; EM; 3.40 A; B=1-467. DR PDB; 8X52; EM; 2.90 A; B=1-467. DR PDB; 8X53; EM; 3.00 A; B=1-467. DR PDB; 8X54; EM; 2.90 A; B=1-467. DR PDBsum; 2KR6; -. DR PDBsum; 4UIS; -. DR PDBsum; 5A63; -. DR PDBsum; 5FN2; -. DR PDBsum; 5FN3; -. DR PDBsum; 5FN4; -. DR PDBsum; 5FN5; -. DR PDBsum; 6IDF; -. DR PDBsum; 6IYC; -. DR PDBsum; 6LQG; -. DR PDBsum; 6LR4; -. DR PDBsum; 7C9I; -. DR PDBsum; 7D8X; -. DR PDBsum; 7Y5T; -. DR PDBsum; 8IM7; -. DR PDBsum; 8K8E; -. DR PDBsum; 8KCO; -. DR PDBsum; 8KCP; -. DR PDBsum; 8KCS; -. DR PDBsum; 8KCT; -. DR PDBsum; 8KCU; -. DR PDBsum; 8OQY; -. DR PDBsum; 8OQZ; -. DR PDBsum; 8X52; -. DR PDBsum; 8X53; -. DR PDBsum; 8X54; -. DR AlphaFoldDB; P49768; -. DR EMDB; EMD-0944; -. DR EMDB; EMD-0957; -. DR EMDB; EMD-17112; -. DR EMDB; EMD-17113; -. DR EMDB; EMD-2477; -. DR EMDB; EMD-2478; -. DR EMDB; EMD-30312; -. DR EMDB; EMD-30614; -. DR EMDB; EMD-33624; -. DR EMDB; EMD-35572; -. DR EMDB; EMD-36948; -. DR EMDB; EMD-37106; -. DR EMDB; EMD-37107; -. DR EMDB; EMD-37108; -. DR EMDB; EMD-37109; -. DR EMDB; EMD-37110; -. DR EMDB; EMD-38059; -. DR EMDB; EMD-38060; -. DR EMDB; EMD-38061; -. DR EMDB; EMD-9648; -. DR EMDB; EMD-9751; -. DR SMR; P49768; -. DR BioGRID; 111642; 203. DR ComplexPortal; CPX-2176; Gamma-secretase complex, APH1A-PSEN1 variant. DR ComplexPortal; CPX-4233; Gamma-secretase complex, APH1B-PSEN1 variant. DR CORUM; P49768; -. DR DIP; DIP-1134N; -. DR ELM; P49768; -. DR FunCoup; P49768; 2287. DR IntAct; P49768; 299. DR MINT; P49768; -. DR STRING; 9606.ENSP00000326366; -. DR BindingDB; P49768; -. DR ChEMBL; CHEMBL2473; -. DR DrugBank; DB11893; Avagacestat. DR DrugBank; DB12263; Begacestat. DR DrugBank; DB05171; E-2012. DR DrugBank; DB16159; Esflurbiprofen. DR DrugBank; DB12819; GSI-136. DR DrugBank; DB16825; Itanapraced. DR DrugBank; DB12852; MK-0752. DR DrugBank; DB12005; Nirogacestat. DR DrugBank; DB11870; RG-4733. DR DrugBank; DB12463; Semagacestat. DR DrugBank; DB05289; Tarenflurbil. DR GuidetoPHARMACOLOGY; 2402; -. DR MEROPS; A22.001; -. DR TCDB; 1.A.54.1.1; the presenilin er ca(2+) leak channel (presenilin) family. DR iPTMnet; P49768; -. DR PhosphoSitePlus; P49768; -. DR SwissPalm; P49768; -. DR BioMuta; PSEN1; -. DR DMDM; 1709856; -. DR jPOST; P49768; -. DR MassIVE; P49768; -. DR PaxDb; 9606-ENSP00000326366; -. DR PeptideAtlas; P49768; -. DR ProteomicsDB; 56106; -. [P49768-1] DR ProteomicsDB; 56107; -. [P49768-2] DR ProteomicsDB; 56108; -. [P49768-3] DR ProteomicsDB; 56109; -. [P49768-4] DR ProteomicsDB; 56110; -. [P49768-5] DR ProteomicsDB; 56111; -. [P49768-6] DR ProteomicsDB; 56112; -. [P49768-7] DR Pumba; P49768; -. DR Antibodypedia; 3480; 972 antibodies from 47 providers. DR DNASU; 5663; -. DR Ensembl; ENST00000324501.10; ENSP00000326366.5; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000357710.8; ENSP00000350342.4; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000394157.7; ENSP00000377712.3; ENSG00000080815.21. [P49768-4] DR Ensembl; ENST00000394164.5; ENSP00000377719.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000553599.6; ENSP00000452477.2; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000553855.5; ENSP00000452242.1; ENSG00000080815.21. [P49768-5] DR Ensembl; ENST00000554131.6; ENSP00000451915.2; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000555386.6; ENSP00000450845.1; ENSG00000080815.21. [P49768-3] DR Ensembl; ENST00000556951.6; ENSP00000450551.2; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000557511.5; ENSP00000451429.1; ENSG00000080815.21. [P49768-6] DR Ensembl; ENST00000700265.1; ENSP00000514901.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700267.1; ENSP00000514903.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700268.1; ENSP00000514904.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700269.1; ENSP00000514905.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700273.1; ENSP00000514908.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700306.1; ENSP00000514933.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700313.1; ENSP00000514940.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700317.1; ENSP00000514944.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700321.1; ENSP00000514948.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700322.1; ENSP00000514949.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700323.1; ENSP00000514950.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700324.1; ENSP00000514951.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700375.1; ENSP00000514966.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700378.1; ENSP00000514968.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700389.1; ENSP00000514970.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700436.1; ENSP00000514987.1; ENSG00000080815.21. [P49768-5] DR Ensembl; ENST00000700469.1; ENSP00000515002.1; ENSG00000080815.21. [P49768-2] DR GeneID; 5663; -. DR KEGG; hsa:5663; -. DR MANE-Select; ENST00000324501.10; ENSP00000326366.5; NM_000021.4; NP_000012.1. DR UCSC; uc001xnq.5; human. [P49768-1] DR AGR; HGNC:9508; -. DR ClinPGx; PA33855; -. DR CTD; 5663; -. DR DisGeNET; 5663; -. DR GeneCards; PSEN1; -. DR GeneReviews; PSEN1; -. DR HGNC; HGNC:9508; PSEN1. DR HPA; ENSG00000080815; Low tissue specificity. DR MalaCards; PSEN1; -. DR MIM; 104311; gene. DR MIM; 172700; phenotype. DR MIM; 600274; phenotype. DR MIM; 607822; phenotype. DR MIM; 613694; phenotype. DR MIM; 613737; phenotype. DR OpenTargets; ENSG00000080815; -. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 1020; Early-onset autosomal dominant Alzheimer disease. DR Orphanet; 154; Familial isolated dilated cardiomyopathy. DR Orphanet; 100070; Progressive non-fluent aphasia. DR Orphanet; 100069; Semantic dementia. DR VEuPathDB; HostDB:ENSG00000080815; -. DR eggNOG; KOG2736; Eukaryota. DR GeneTree; ENSGT00940000158751; -. DR HOGENOM; CLU_022975_3_0_1; -. DR InParanoid; P49768; -. DR OMA; NATCNQQ; -. DR OrthoDB; 20287at2759; -. DR PAN-GO; P49768; 26 GO annotations based on evolutionary models. DR PhylomeDB; P49768; -. DR PathwayCommons; P49768; -. DR Reactome; R-HSA-1251985; Nuclear signaling by ERBB4. DR Reactome; R-HSA-1474228; Degradation of the extracellular matrix. DR Reactome; R-HSA-193692; Regulated proteolysis of p75NTR. DR Reactome; R-HSA-205043; NRIF signals cell death from the nucleus. DR Reactome; R-HSA-2122948; Activated NOTCH1 Transmits Signal to the Nucleus. DR Reactome; R-HSA-2644606; Constitutive Signaling by NOTCH1 PEST Domain Mutants. DR Reactome; R-HSA-2894862; Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants. DR Reactome; R-HSA-2979096; NOTCH2 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-3928665; EPH-ephrin mediated repulsion of cells. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR Reactome; R-HSA-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-9013700; NOTCH4 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-9017802; Noncanonical activation of NOTCH3. DR Reactome; R-HSA-9839383; TGFBR3 PTM regulation. DR SignaLink; P49768; -. DR SIGNOR; P49768; -. DR Agora; ENSG00000080815; -. DR BioGRID-ORCS; 5663; 16 hits in 1162 CRISPR screens. DR CD-CODE; 8C2F96ED; Centrosome. DR ChiTaRS; PSEN1; human. DR EvolutionaryTrace; P49768; -. DR GeneWiki; PSEN1; -. DR GenomeRNAi; 5663; -. DR Pharos; P49768; Tchem. DR PRO; PR:P49768; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; P49768; protein. DR Bgee; ENSG00000080815; Expressed in middle frontal gyrus and 202 other cell types or tissues. DR ExpressionAtlas; P49768; baseline and differential. DR GO; GO:0016235; C:aggresome; IDA:UniProtKB. DR GO; GO:0035577; C:azurophil granule membrane; TAS:Reactome. DR GO; GO:0005938; C:cell cortex; IEA:Ensembl. DR GO; GO:0030054; C:cell junction; IDA:HPA. DR GO; GO:0009986; C:cell surface; IEA:Ensembl. DR GO; GO:0005813; C:centrosome; IDA:UniProtKB. DR GO; GO:0035253; C:ciliary rootlet; IEA:Ensembl. DR GO; GO:0030425; C:dendrite; IDA:ARUK-UCL. DR GO; GO:0043198; C:dendritic shaft; IEA:Ensembl. DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HGNC-UCL. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0070765; C:gamma-secretase complex; IDA:UniProtKB. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0030426; C:growth cone; IDA:UniProtKB. DR GO; GO:0000776; C:kinetochore; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0045121; C:membrane raft; IDA:UniProtKB. DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:Ensembl. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0031594; C:neuromuscular junction; IEA:Ensembl. DR GO; GO:0043005; C:neuron projection; IDA:UniProtKB. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0031965; C:nuclear membrane; IDA:UniProtKB. DR GO; GO:0005640; C:nuclear outer membrane; IDA:MGI. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IMP:CAFA. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0098794; C:postsynapse; IEA:GOC. DR GO; GO:0042734; C:presynaptic membrane; IEA:Ensembl. DR GO; GO:0032991; C:protein-containing complex; IMP:CAFA. DR GO; GO:0005791; C:rough endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0042383; C:sarcolemma; IEA:Ensembl. DR GO; GO:0005790; C:smooth endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0008021; C:synaptic vesicle; IEA:Ensembl. DR GO; GO:0042500; F:aspartic endopeptidase activity, intramembrane cleaving; IDA:UniProtKB. DR GO; GO:0004190; F:aspartic-type endopeptidase activity; NAS:ARUK-UCL. DR GO; GO:0051117; F:ATPase binding; IPI:ARUK-UCL. DR GO; GO:0008013; F:beta-catenin binding; IPI:UniProtKB. DR GO; GO:0045296; F:cadherin binding; IEA:Ensembl. DR GO; GO:0005262; F:calcium channel activity; IMP:UniProtKB. DR GO; GO:0004175; F:endopeptidase activity; IDA:MGI. DR GO; GO:0070851; F:growth factor receptor binding; IPI:ARUK-UCL. DR GO; GO:0060090; F:molecular adaptor activity; IDA:UniProtKB. DR GO; GO:0030165; F:PDZ domain binding; IPI:UniProtKB. DR GO; GO:0042987; P:amyloid precursor protein catabolic process; IDA:ARUK-UCL. DR GO; GO:0042982; P:amyloid precursor protein metabolic process; IDA:UniProtKB. DR GO; GO:0034205; P:amyloid-beta formation; IDA:ARUK-UCL. DR GO; GO:0097190; P:apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0048143; P:astrocyte activation; IGI:ARUK-UCL. DR GO; GO:0002265; P:astrocyte activation involved in immune response; IGI:ARUK-UCL. DR GO; GO:0000045; P:autophagosome assembly; IEA:Ensembl. DR GO; GO:0001568; P:blood vessel development; IEA:Ensembl. DR GO; GO:0048854; P:brain morphogenesis; IEA:Ensembl. DR GO; GO:0021870; P:Cajal-Retzius cell differentiation; IEA:Ensembl. DR GO; GO:0055074; P:calcium ion homeostasis; IBA:GO_Central. DR GO; GO:0001708; P:cell fate specification; IEA:Ensembl. DR GO; GO:0098609; P:cell-cell adhesion; IMP:MGI. DR GO; GO:1904646; P:cellular response to amyloid-beta; IGI:ARUK-UCL. DR GO; GO:0021549; P:cerebellum development; IEA:Ensembl. DR GO; GO:0021795; P:cerebral cortex cell migration; IEA:Ensembl. DR GO; GO:0015871; P:choline transport; IEA:Ensembl. DR GO; GO:0006974; P:DNA damage response; IDA:ARUK-UCL. DR GO; GO:0021904; P:dorsal/ventral neural tube patterning; IEA:Ensembl. DR GO; GO:0030326; P:embryonic limb morphogenesis; IEA:Ensembl. DR GO; GO:0032469; P:endoplasmic reticulum calcium ion homeostasis; IDA:MGI. DR GO; GO:0050673; P:epithelial cell proliferation; IEA:Ensembl. DR GO; GO:0001947; P:heart looping; IEA:Ensembl. DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IEA:Ensembl. DR GO; GO:0035556; P:intracellular signal transduction; IMP:UniProtKB. DR GO; GO:0098712; P:L-glutamate import across plasma membrane; IEA:Ensembl. DR GO; GO:0007611; P:learning or memory; IGI:ARUK-UCL. DR GO; GO:0040011; P:locomotion; IEA:Ensembl. DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IDA:HGNC-UCL. DR GO; GO:0007613; P:memory; IGI:ARUK-UCL. DR GO; GO:0006839; P:mitochondrial transport; IEA:Ensembl. DR GO; GO:0043011; P:myeloid dendritic cell differentiation; IEA:Ensembl. DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:2001234; P:negative regulation of apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0050771; P:negative regulation of axonogenesis; IEA:Ensembl. DR GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; IEA:Ensembl. DR GO; GO:0010629; P:negative regulation of gene expression; IGI:ARUK-UCL. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:2000059; P:negative regulation of ubiquitin-dependent protein catabolic process; IEA:Ensembl. DR GO; GO:0003407; P:neural retina development; IEA:Ensembl. DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl. DR GO; GO:0070050; P:neuron cellular homeostasis; IEA:Ensembl. DR GO; GO:0048666; P:neuron development; IEA:Ensembl. DR GO; GO:0001764; P:neuron migration; IEA:Ensembl. DR GO; GO:1990535; P:neuron projection maintenance; IGI:ARUK-UCL. DR GO; GO:0007220; P:Notch receptor processing; IDA:ARUK-UCL. DR GO; GO:0007219; P:Notch signaling pathway; IBA:GO_Central. DR GO; GO:1905908; P:positive regulation of amyloid fibril formation; IGI:ARUK-UCL. DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0050820; P:positive regulation of coagulation; IEA:Ensembl. DR GO; GO:0060999; P:positive regulation of dendritic spine development; IMP:CACAO. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IMP:CACAO. DR GO; GO:0010628; P:positive regulation of gene expression; IGI:ARUK-UCL. DR GO; GO:0045821; P:positive regulation of glycolytic process; IGI:ARUK-UCL. DR GO; GO:0002038; P:positive regulation of L-glutamate import across plasma membrane; IEA:Ensembl. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IEA:Ensembl. DR GO; GO:0001921; P:positive regulation of receptor recycling; IEA:Ensembl. DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IGI:ARUK-UCL. DR GO; GO:0009791; P:post-embryonic development; IEA:Ensembl. DR GO; GO:0140249; P:protein catabolic process at postsynapse; IEA:Ensembl. DR GO; GO:0016485; P:protein processing; IDA:HGNC-UCL. DR GO; GO:0015031; P:protein transport; IEA:Ensembl. DR GO; GO:0060828; P:regulation of canonical Wnt signaling pathway; ISS:UniProtKB. DR GO; GO:0010468; P:regulation of gene expression; IGI:ARUK-UCL. DR GO; GO:0010975; P:regulation of neuron projection development; IMP:UniProtKB. DR GO; GO:0099175; P:regulation of postsynapse organization; IEA:Ensembl. DR GO; GO:0060075; P:regulation of resting membrane potential; IEA:Ensembl. DR GO; GO:0048167; P:regulation of synaptic plasticity; IEA:Ensembl. DR GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; IEA:Ensembl. DR GO; GO:0098693; P:regulation of synaptic vesicle cycle; IEA:Ensembl. DR GO; GO:0006979; P:response to oxidative stress; IEA:Ensembl. DR GO; GO:0051208; P:sequestering of calcium ion; IEA:Ensembl. DR GO; GO:0048705; P:skeletal system morphogenesis; IEA:Ensembl. DR GO; GO:0043589; P:skin morphogenesis; IEA:Ensembl. DR GO; GO:0051563; P:smooth endoplasmic reticulum calcium ion homeostasis; IEA:Ensembl. DR GO; GO:0001756; P:somitogenesis; IEA:Ensembl. DR GO; GO:0050808; P:synapse organization; IGI:ARUK-UCL. DR GO; GO:0016080; P:synaptic vesicle targeting; IEA:Ensembl. DR GO; GO:0002286; P:T cell activation involved in immune response; IEA:Ensembl. DR GO; GO:0050852; P:T cell receptor signaling pathway; IEA:Ensembl. DR GO; GO:0048538; P:thymus development; IEA:Ensembl. DR DisProt; DP01292; -. DR FunFam; 1.10.472.100:FF:000001; Presenilin; 1. DR Gene3D; 1.10.472.100; Presenilin; 1. DR InterPro; IPR002031; Pept_A22A_PS1. DR InterPro; IPR001108; Peptidase_A22A. DR InterPro; IPR006639; Preselin/SPP. DR InterPro; IPR042524; Presenilin_C. DR PANTHER; PTHR10202; PRESENILIN; 1. DR PANTHER; PTHR10202:SF18; PRESENILIN-1; 1. DR Pfam; PF01080; Presenilin; 1. DR PRINTS; PR01072; PRESENILIN. DR PRINTS; PR01073; PRESENILIN1. DR SMART; SM00730; PSN; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Alzheimer disease; Amyloidosis; KW Apoptosis; Cardiomyopathy; Cell adhesion; Cell membrane; Cell projection; KW Direct protein sequencing; Disease variant; Endoplasmic reticulum; KW Endosome; Golgi apparatus; Hydrolase; Membrane; Neurodegeneration; KW Notch signaling pathway; Phosphoprotein; Protease; KW Proteomics identification; Reference proteome; Synapse; Transmembrane; KW Transmembrane helix. FT CHAIN 1..298 FT /note="Presenilin-1 NTF subunit" FT /evidence="ECO:0000269|PubMed:9173929" FT /id="PRO_0000025591" FT CHAIN 299..467 FT /note="Presenilin-1 CTF subunit" FT /evidence="ECO:0000269|PubMed:9173929" FT /id="PRO_0000025592" FT CHAIN 346..467 FT /note="Presenilin-1 CTF12" FT /evidence="ECO:0000269|PubMed:9485372" FT /id="PRO_0000236055" FT TOPO_DOM 1..82 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 83..103 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 104..132 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 133..153 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 154..166 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 167..189 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 190..194 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 195..216 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 217..220 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 221..241 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 242..248 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 249..272 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 273..380 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 381..401 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 402..407 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 408..428 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 429..432 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 433..453 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 454..467 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT REGION 13..68 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 288..290 FT /note="Important for cleavage of target proteins" FT /evidence="ECO:0000269|PubMed:30598546" FT REGION 305..333 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 322..450 FT /note="Required for interaction with CTNNB1" FT /evidence="ECO:0000269|PubMed:9738936" FT REGION 372..399 FT /note="Required for interaction with CTNND2" FT /evidence="ECO:0000269|PubMed:10037471" FT REGION 377..381 FT /note="Important for cleavage of target proteins" FT /evidence="ECO:0000269|PubMed:30598546" FT REGION 432..434 FT /note="Important for cleavage of target proteins" FT /evidence="ECO:0000269|PubMed:30598546" FT REGION 464..467 FT /note="Interaction with MTCH1" FT /evidence="ECO:0000269|PubMed:10551805" FT MOTIF 433..435 FT /note="PAL" FT /evidence="ECO:0000305|PubMed:16305624" FT COMPBIAS 13..29 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 30..45 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 257 FT /evidence="ECO:0000305|PubMed:10206644, FT ECO:0000305|PubMed:10899933, ECO:0000305|PubMed:15341515" FT ACT_SITE 385 FT /evidence="ECO:0000305|PubMed:10206644, FT ECO:0000305|PubMed:10899933, ECO:0000305|PubMed:15341515, FT ECO:0000305|PubMed:30598546, ECO:0000305|PubMed:30630874" FT SITE 291..292 FT /note="Cleavage; alternate" FT /evidence="ECO:0000269|PubMed:9173929" FT SITE 292..293 FT /note="Cleavage; alternate" FT /evidence="ECO:0000269|PubMed:9173929" FT SITE 298..299 FT /note="Cleavage" FT /evidence="ECO:0000269|PubMed:9173929" FT SITE 345..346 FT /note="Cleavage; by caspase" FT /evidence="ECO:0000269|PubMed:9485372" FT MOD_RES 43 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17081983, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 51 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P97887" FT MOD_RES 310 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000269|PubMed:14576165" FT MOD_RES 346 FT /note="Phosphoserine; by PKC" FT /evidence="ECO:0000269|PubMed:14576165" FT MOD_RES 367 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT VAR_SEQ 26..29 FT /note="Missing (in isoform 2 and isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:7596406, ECO:0000303|PubMed:8641442" FT /id="VSP_005191" FT VAR_SEQ 162..184 FT /note="IHAWLIISSLLLLFFFSFIYLGE -> SMRHRSLLSTLFFLWLGILVTVT FT (in isoform 4)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_007986" FT VAR_SEQ 185..467 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_007987" FT VAR_SEQ 257..289 FT /note="Missing (in isoform 7)" FT /evidence="ECO:0000305" FT /id="VSP_041440" FT VAR_SEQ 319..467 FT /note="STERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAAVQELSSSILA FT GEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCLTLLLLAIFK FT KALPALPISITFGLVFYFATDYLVQPFMDQLAFHQFYI -> RACLPPAAINLLSIAPM FT APRLFMPKGACRPTAQKGSHKTLLQRMMMAGSVRNGKPRGTVI (in isoform 3 FT and isoform 5)" FT /evidence="ECO:0000303|PubMed:8641442, ECO:0000303|Ref.5" FT /id="VSP_005192" FT VAR_SEQ 319..376 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000305" FT /id="VSP_012288" FT VARIANT 35 FT /note="R -> Q (in AD3; uncertain significance; decreased FT protease activity with APP; dbSNP:rs63750592)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075260" FT VARIANT 79 FT /note="A -> V (in AD3; also found in late-onset Alzheimer FT disease; impaired protease activity with APP; results in FT altered amyloid-beta production and increased amyloid-beta FT 42/amyloid-beta 40 ratio; no effect on interaction with FT GFAP; dbSNP:rs63749824)" FT /evidence="ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:12058025, FT ECO:0000269|PubMed:16752394, ECO:0000269|PubMed:17366635, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9384602" FT /id="VAR_006413" FT VARIANT 82 FT /note="V -> L (in AD3; decreased protease activity with FT APP; no effect on interaction with GFAP; dbSNP:rs63749967)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:12058025, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634712" FT /id="VAR_006414" FT VARIANT 83 FT /note="I -> T (in AD3)" FT /evidence="ECO:0000269|PubMed:26145164" FT /id="VAR_075261" FT VARIANT 85 FT /note="L -> P (in AD3; the patient also manifest spastic FT paraparesis and apraxia; loss of protease activity with APP FT in vitro; altered amyloid-beta production in cells FT transfected with the mutant and increased amyloid-beta 42/ FT amyloid-beta 40 ratio; dbSNP:rs63750599)" FT /evidence="ECO:0000269|PubMed:15534188, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081228" FT VARIANT 89 FT /note="V -> L (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750815)" FT /evidence="ECO:0000269|PubMed:11796781" FT /id="VAR_081229" FT VARIANT 92 FT /note="C -> S (in AD3; loss of protease activity with APP; FT dbSNP:rs63751141)" FT /evidence="ECO:0000269|PubMed:11027672, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016214" FT VARIANT 94 FT /note="V -> M (in AD3; uncertain significance; reduced FT protease activity with APP; no relevant change in amyloid- FT beta 42/amyloid-beta 40 ratio; dbSNP:rs63750831)" FT /evidence="ECO:0000269|PubMed:11568920" FT /id="VAR_081230" FT VARIANT 96 FT /note="V -> F (in AD3; loss of protease activity with APP; FT dbSNP:rs63750601)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8733303" FT /id="VAR_006415" FT VARIANT 97 FT /note="V -> L (in AD3; uncertain significance; slightly FT reduced protease activity with APP; dbSNP:rs63750852)" FT /evidence="ECO:0000269|PubMed:15851849, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081231" FT VARIANT 105 FT /note="F -> L (in AD3; dbSNP:rs63750321)" FT /evidence="ECO:0000269|PubMed:10631141" FT /id="VAR_009208" FT VARIANT 113 FT /note="L -> P (in FTD1; dbSNP:rs63751399)" FT /evidence="ECO:0000269|PubMed:11094121" FT /id="VAR_016215" FT VARIANT 115 FT /note="Y -> C (in AD3; dbSNP:rs63750450)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:12552037, ECO:0000269|PubMed:9384602" FT /id="VAR_006416" FT VARIANT 115 FT /note="Y -> H (in AD3; impaired protease activity with APP FT and increased amyloid-beta 42/amyloid-beta 40 ratio)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:8634712" FT /id="VAR_006417" FT VARIANT 116 FT /note="T -> I (in AD3; dbSNP:rs63750730)" FT /evidence="ECO:0000269|PubMed:30200536" FT /id="VAR_081232" FT VARIANT 116 FT /note="T -> N (in AD3; unusual amyloid cotton wool plaques FT detected in one patient's brain; severe decrease of FT protease activity with APP; results in increased amyloid- FT beta 42/amyloid-beta 40 ratio; dbSNP:rs63750730)" FT /evidence="ECO:0000269|PubMed:10439444, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:29404783" FT /id="VAR_010120" FT VARIANT 117 FT /note="P -> L (in AD3; impaired ability to cleave Ephb2/ FT CTF1; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; impaired FT regulation of neurite outgrowth; dbSNP:rs63749805)" FT /evidence="ECO:0000269|PubMed:15004326, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:9507958" FT /id="VAR_009209" FT VARIANT 117 FT /note="P -> S (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; impaired regulation of neurite outgrowth; FT dbSNP:rs63750550)" FT /evidence="ECO:0000269|PubMed:15004326" FT /id="VAR_081233" FT VARIANT 120 FT /note="E -> D (in AD3; impaired protease activity with APP FT and increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751272)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9521423" FT /id="VAR_006418" FT VARIANT 120 FT /note="E -> K (in AD3; impaired protease activity with APP FT and increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750800)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_006419" FT VARIANT 134 FT /note="L -> R (in AD3; uncertain significance; loss of FT protease activity with APP; dbSNP:rs1595002439)" FT /evidence="ECO:0000269|PubMed:22503161, FT ECO:0000269|PubMed:27930341" FT /id="VAR_070023" FT VARIANT 135 FT /note="N -> D (in AD3; impaired protease activity with APP FT and increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750353)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:9225696" FT /id="VAR_010121" FT VARIANT 139 FT /note="M -> I (in AD3; dbSNP:rs63750522)" FT /evidence="ECO:0000269|PubMed:8875251" FT /id="VAR_006420" FT VARIANT 139 FT /note="M -> K (in AD3; dbSNP:rs63751106)" FT /evidence="ECO:0000269|PubMed:9719376" FT /id="VAR_010122" FT VARIANT 139 FT /note="M -> T (in AD3; dbSNP:rs63751106)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:8634712" FT /id="VAR_006421" FT VARIANT 139 FT /note="M -> V (in AD3; increased amyloid-beta 42/amyloid- FT beta 40 ratio; dbSNP:rs63751037)" FT /evidence="ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7550356" FT /id="VAR_006422" FT VARIANT 142 FT /note="V -> F (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:29175279" FT /id="VAR_081234" FT VARIANT 143 FT /note="I -> F (in AD3; dbSNP:rs63750322)" FT /evidence="ECO:0000269|PubMed:10090481" FT /id="VAR_006423" FT VARIANT 143 FT /note="I -> T (in AD3; impaired protease activity with APP; FT results in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750004)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:11568920, ECO:0000269|PubMed:15122701, FT ECO:0000269|PubMed:16752394, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634711" FT /id="VAR_006424" FT VARIANT 146 FT /note="M -> I (in AD3; dbSNP:rs63750391)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:12552037" FT /id="VAR_006425" FT VARIANT 146 FT /note="M -> L (in AD3; disease phenotype shows high FT clinical variability; founder mutation originating from FT Southern Italy and distributed worldwide; alters the FT conformation of the active site; slightly increased FT protease activity with APP; decreased activity for Notch1 FT cleavage; no loss of its ability to cleave Ephb2/CTF1; FT dbSNP:rs63750306)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:17428795, FT ECO:0000269|PubMed:20164095, ECO:0000269|PubMed:22461631, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7596406" FT /id="VAR_006426" FT VARIANT 146 FT /note="M -> V (in AD3; loss of function as calcium-leak FT channel; results in calcium overload in the endoplasmic FT reticulum; dbSNP:rs63750306)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:16959576, ECO:0000269|PubMed:7550356" FT /id="VAR_006427" FT VARIANT 147 FT /note="T -> I (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750907)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341" FT /id="VAR_010123" FT VARIANT 153 FT /note="L -> V (in AD3; abolishes protease activity with APP FT resulting in decreased amyloid-beta 42 and amyloid-beta 40 FT production; dbSNP:rs63751441)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:24495933, ECO:0000269|PubMed:27930341" FT /id="VAR_081235" FT VARIANT 154 FT /note="Y -> C (in AD3; uncertain significance; FT dbSNP:rs63751292)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_081236" FT VARIANT 154 FT /note="Y -> N (in AD3; disease phenotype includes spastic FT paraparesis; abolishes protease activity with APP resulting FT in decreased amyloid-beta 42 and amyloid-beta 40 FT production; dbSNP:rs63750588)" FT /evidence="ECO:0000269|PubMed:15364419, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081237" FT VARIANT 156 FT /note="Y -> FTY (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075262" FT VARIANT 159 FT /note="Y -> F (in AD3; uncertain significance; FT dbSNP:rs778630379)" FT /evidence="ECO:0000269|PubMed:23123781" FT /id="VAR_081238" FT VARIANT 163 FT /note="H -> R (in AD3; abolishes protease activity with FT APP; decreased activity for Notch cleavage; FT dbSNP:rs63750590)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:22461631, FT ECO:0000269|PubMed:22503161, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:8634712, FT ECO:0000269|PubMed:8733303, ECO:0000269|PubMed:9521423" FT /id="VAR_006428" FT VARIANT 163 FT /note="H -> Y (in AD3; slightly increased protease activity FT with APP and slightly increased amyloid-beta 42 production; FT dbSNP:rs63749885)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7550356" FT /id="VAR_006429" FT VARIANT 165 FT /note="W -> C (in AD3; dbSNP:rs63751484)" FT /evidence="ECO:0000269|PubMed:10441572" FT /id="VAR_010124" FT VARIANT 166 FT /note="L -> P (in AD3; onset in adolescence; severe FT decrease of protease activity with APP; results in altered FT amyloid-beta production and increased amyloid-beta 42/ FT amyloid-beta 40 ratio; results in reduced Notch FT proteolysis; dbSNP:rs63750265)" FT /evidence="ECO:0000269|PubMed:12048239, FT ECO:0000269|PubMed:22529981, ECO:0000269|PubMed:23843529, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016216" FT VARIANT 168 FT /note="Missing (in AD3; uncertain significance; abolishes FT protease activity with APP resulting in decreased amyloid- FT beta 42 and amyloid-beta 40 production)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_081239" FT VARIANT 169 FT /note="S -> L (in AD3; dbSNP:rs63751210)" FT /evidence="ECO:0000269|PubMed:9831473" FT /id="VAR_006430" FT VARIANT 169 FT /note="S -> P (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750418)" FT /evidence="ECO:0000269|PubMed:10025789, FT ECO:0000269|PubMed:27930341" FT /id="VAR_006431" FT VARIANT 170 FT /note="S -> F (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750577)" FT /evidence="ECO:0000269|PubMed:16344340, FT ECO:0000269|PubMed:17502474, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:29466804" FT /id="VAR_081240" FT VARIANT 171 FT /note="L -> P (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750963)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9833068" FT /id="VAR_006432" FT VARIANT 173 FT /note="L -> W (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750299)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341" FT /id="VAR_010125" FT VARIANT 174 FT /note="L -> M (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63751144)" FT /evidence="ECO:0000269|PubMed:12484344, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016217" FT VARIANT 177 FT /note="F -> L (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63749911)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075263" FT VARIANT 177 FT /note="F -> S (in AD3; uncertain significance; FT dbSNP:rs63749806)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075264" FT VARIANT 178 FT /note="S -> P (in AD3; uncertain significance; abolishes FT protease activity with APP; dbSNP:rs63750155)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075265" FT VARIANT 183 FT /note="G -> V (in PIDB and AD3; uncertain significance; FT neuropathologic examination of brain sections from a FT patient shows the presence of Pick bodies and absence of FT beta-amyloid plaques; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio in vitro; dbSNP:rs63751068)" FT /evidence="ECO:0000269|PubMed:15122701, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081241" FT VARIANT 184 FT /note="E -> D (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750311)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081242" FT VARIANT 205 FT /note="F -> L (in dbSNP:rs1042864)" FT /id="VAR_011876" FT VARIANT 206 FT /note="G -> A (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750082)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:11710891, ECO:0000269|PubMed:27073747, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016218" FT VARIANT 206 FT /note="G -> D (in AD3; affects APP processing resulting in FT increased amyloid-beta 42/amyloid-beta 40 ratio; does not FT affect NOTCH processing; does not affect endoproteolysis; FT reduced interaction with PEN2; results in decreased protein FT levels in the endoplasmic reticulum but increased levels in FT early endosome; reduced ability to maintain ER calcium FT homeostasis; dbSNP:rs63750082)" FT /evidence="ECO:0000269|PubMed:21335660, FT ECO:0000269|PubMed:25394380, ECO:0000269|PubMed:29175279" FT /id="VAR_081243" FT VARIANT 206 FT /note="G -> S (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750569)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075266" FT VARIANT 209 FT /note="G -> E (in AD3; uncertain significance; FT dbSNP:rs63750053)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075267" FT VARIANT 209 FT /note="G -> R (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63749880)" FT /evidence="ECO:0000269|PubMed:10447269, FT ECO:0000269|PubMed:27930341" FT /id="VAR_009210" FT VARIANT 209 FT /note="G -> V (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750053)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:9521423" FT /id="VAR_006433" FT VARIANT 213 FT /note="I -> L (in AD3; increases protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750861)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341" FT /id="VAR_075268" FT VARIANT 213 FT /note="I -> T (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63751309)" FT /evidence="ECO:0000269|PubMed:18430735, FT ECO:0000269|PubMed:8733303" FT /id="VAR_006434" FT VARIANT 214 FT /note="H -> Y (found in a patient with dementia; uncertain FT significance; dbSNP:rs63751003)" FT /evidence="ECO:0000269|PubMed:22503161" FT /id="VAR_070024" FT VARIANT 217 FT /note="G -> R (in AD3; with unusual amyloid cotton wool FT plaques; decreased protease activity with APP resulting in FT altered amyloid-beta production and increased amyloid-beta FT 42/amyloid-beta 40 ratio; dbSNP:rs267606983)" FT /evidence="ECO:0000269|PubMed:19667325, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081244" FT VARIANT 219 FT /note="L -> P (in AD3; dbSNP:rs63750761)" FT /evidence="ECO:0000269|PubMed:10208579" FT /id="VAR_010126" FT VARIANT 222 FT /note="Q -> R (in AD3; uncertain significance; slightly FT increased protease activity with APP and slightly increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750009)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075269" FT VARIANT 229 FT /note="I -> F (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63749970)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081245" FT VARIANT 231 FT /note="A -> T (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63749836)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634712" FT /id="VAR_006435" FT VARIANT 231 FT /note="A -> V (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750799)" FT /evidence="ECO:0000269|PubMed:16752394, FT ECO:0000269|PubMed:9384602" FT /id="VAR_006436" FT VARIANT 233 FT /note="M -> L (in AD3; slightly decreased protease activity FT with APP resulting in altered amyloid-beta production and FT mildly increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751287)" FT /evidence="ECO:0000269|PubMed:10533070, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341" FT /id="VAR_009211" FT VARIANT 233 FT /note="M -> T (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63751024)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9172170" FT /id="VAR_006437" FT VARIANT 235 FT /note="L -> P (in AD3; abolishes protease activity with FT APP; dbSNP:rs63749835)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341" FT /id="VAR_006438" FT VARIANT 235 FT /note="L -> R (in AD3; abolishes protease activity with FT APP)" FT /evidence="ECO:0000269|PubMed:21501661, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081246" FT VARIANT 235 FT /note="L -> V (in AD3; reduced APP cleavage resulting in FT decreased amyloid-beta 42 and amyloid-beta 40 production; FT no relevant change in amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63751130)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081247" FT VARIANT 237 FT /note="F -> I (in AD3; uncertain significance; disease FT phenotype includes spastic paraparesis; severe decrease of FT protease activity with APP; results in decreased amyloid- FT beta 42 and amyloid-beta 40 production; dbSNP:rs63750858)" FT /evidence="ECO:0000269|PubMed:11561050, FT ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341" FT /id="VAR_081248" FT VARIANT 237 FT /note="F -> L (in AD3; uncertain significance; FT dbSNP:rs63750858)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_081249" FT VARIANT 246 FT /note="A -> E (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT no loss of its ability to cleave Ephb2/CTF1; FT dbSNP:rs63750526)" FT /evidence="ECO:0000269|PubMed:17428795, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7596406" FT /id="VAR_006439" FT VARIANT 250 FT /note="L -> S (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751163)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_006440" FT VARIANT 260 FT /note="A -> V (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT impaired ability to cleave Ephb2/CTF1; dbSNP:rs63751420)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:9521423" FT /id="VAR_006441" FT VARIANT 261 FT /note="V -> F (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750964)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341" FT /id="VAR_075270" FT VARIANT 262 FT /note="L -> F (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750248)" FT /evidence="ECO:0000269|PubMed:16752394, FT ECO:0000269|PubMed:27930341" FT /id="VAR_006442" FT VARIANT 262 FT /note="L -> V (in AD3)" FT /evidence="ECO:0000269|PubMed:22503161" FT /id="VAR_070025" FT VARIANT 263 FT /note="C -> F (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63751102)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:16752394" FT /id="VAR_081250" FT VARIANT 263 FT /note="C -> R (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750543)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_006443" FT VARIANT 264 FT /note="P -> L (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT impaired ability to cleave Ephb2/CTF1; dbSNP:rs63750301)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634712, ECO:0000269|PubMed:9521423" FT /id="VAR_006444" FT VARIANT 266 FT /note="G -> S (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs121917807)" FT /evidence="ECO:0000269|PubMed:11920851, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016219" FT VARIANT 267 FT /note="P -> S (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751229)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7550356" FT /id="VAR_006445" FT VARIANT 269 FT /note="R -> G (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751019)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_006447" FT VARIANT 269 FT /note="R -> H (in AD3; dbSNP:rs63750900)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_006448" FT VARIANT 271 FT /note="L -> V (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750886)" FT /evidence="ECO:0000269|PubMed:12493737, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016220" FT VARIANT 274 FT /note="T -> R (in AD3; uncertain significance; abolishes FT protease activity with APP; dbSNP:rs63750284)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075271" FT VARIANT 275 FT /note="A -> V (in AD3; uncertain significance; reduced FT protease activity with APP resulting in reduced amyloid- FT beta 40 levels but no relevant changes in amyloid-beta 42/ FT amyloid-beta 40 ratio; dbSNP:rs1555355869)" FT /evidence="ECO:0000269|PubMed:24582897, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081251" FT VARIANT 278 FT /note="R -> I (in AD3; atypical phenotype presenting as FT language impairment, impaired frontal executive function FT and relative preservation of memory; severe decrease of APP FT and Notch proteolysis; dbSNP:rs63749891)" FT /evidence="ECO:0000269|PubMed:15534260, FT ECO:0000269|PubMed:23843529" FT /id="VAR_081252" FT VARIANT 278 FT /note="R -> T (in AD3; dbSNP:rs63749891)" FT /evidence="ECO:0000269|PubMed:9172170" FT /id="VAR_006449" FT VARIANT 280 FT /note="E -> A (in AD3; strong deposition of amyloid-beta 42 FT is observed in brain regions of AD3 patients; decreased FT protease activity with APP resulting in altered amyloid- FT beta production and increased amyloid-beta 42/amyloid-beta FT 40 ratio; decreased activity for Notch1 cleavage; FT dbSNP:rs63750231)" FT /evidence="ECO:0000269|PubMed:11568920, FT ECO:0000269|PubMed:22461631, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:28269784, ECO:0000269|PubMed:7550356, FT ECO:0000269|PubMed:8837617, ECO:0000269|PubMed:9298817" FT /id="VAR_006450" FT VARIANT 280 FT /note="E -> G (in AD3; some AD3 patients manifest spastic FT paraparesis and unusual amyloid plaques with prominent FT amyloid angiopathy on brain biopsy; decreased protease FT activity with APP; increased amyloid-beta 42/amyloid-beta FT 40 ratio; impaired ability to cleave Ephb2/CTF1; FT dbSNP:rs63750231)" FT /evidence="ECO:0000269|PubMed:12370477, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7550356" FT /id="VAR_006451" FT VARIANT 282 FT /note="L -> R (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750050)" FT /evidence="ECO:0000269|PubMed:10533070, FT ECO:0000269|PubMed:27930341" FT /id="VAR_009212" FT VARIANT 282 FT /note="L -> V (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63749937)" FT /evidence="ECO:0000269|PubMed:11701593, FT ECO:0000269|PubMed:15122701, ECO:0000269|PubMed:16752394" FT /id="VAR_081253" FT VARIANT 285 FT /note="A -> V (in AD3; slightly decreased protease activity FT with APP and slightly decreased amyloid-beta 42/amyloid- FT beta 40 ratio; dbSNP:rs63751139)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7651536" FT /id="VAR_006452" FT VARIANT 286 FT /note="L -> V (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63751235)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7596406" FT /id="VAR_006453" FT VARIANT 289 FT /note="S -> C (in AD3)" FT /evidence="ECO:0000269|PubMed:8875251" FT /id="VAR_010127" FT VARIANT 311 FT /note="K -> R (found in patients with late-onset Alzheimer FT disease; uncertain significance; results in altered FT amyloid-beta production and increased amyloid-beta 42/ FT amyloid-beta 40 ratio; dbSNP:rs115865530)" FT /evidence="ECO:0000269|PubMed:28269784" FT /id="VAR_081254" FT VARIANT 315 FT /note="Y -> C (found in a renal cell carcinoma sample; FT somatic mutation)" FT /evidence="ECO:0000269|PubMed:21248752" FT /id="VAR_064747" FT VARIANT 318 FT /note="E -> G (in dbSNP:rs17125721)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:10533070, ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:11568920, FT ECO:0000269|PubMed:12552037, ECO:0000269|PubMed:18485326, FT ECO:0000269|PubMed:9384602, ECO:0000269|PubMed:9851443, FT ECO:0000269|PubMed:9851450, ECO:0000269|PubMed:9915968" FT /id="VAR_006454" FT VARIANT 333 FT /note="D -> G (in CMD1U; results in slightly decreased FT protease activity with APP and slightly decreased amyloid- FT beta 42/amyloid-beta 40 ratio; dbSNP:rs121917809)" FT /evidence="ECO:0000269|PubMed:17186461, FT ECO:0000269|PubMed:27930341" FT /id="VAR_064902" FT VARIANT 352 FT /note="R -> RR (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075272" FT VARIANT 354 FT /note="T -> I (in AD3; uncertain significance; results in FT decreased protease activity with APP and decreased amyloid- FT beta 42/amyloid-beta 40 ratio; dbSNP:rs63751164)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075273" FT VARIANT 358 FT /note="R -> Q (in AD3; uncertain significance; results in FT altered amyloid-beta production and increased amyloid-beta FT 42/amyloid-beta 40 ratio; dbSNP:rs63751174)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075274" FT VARIANT 365 FT /note="S -> Y (in AD3; uncertain significance; FT dbSNP:rs63750941)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075275" FT VARIANT 377 FT /note="R -> M (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_081255" FT VARIANT 378 FT /note="G -> E (in AD3; decreased protease activity with FT APP; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio)" FT /evidence="ECO:0000269|PubMed:10200054, FT ECO:0000269|PubMed:27930341" FT /id="VAR_006455" FT VARIANT 378 FT /note="G -> V (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750323)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27073747, ECO:0000269|PubMed:27930341" FT /id="VAR_081256" FT VARIANT 381 FT /note="L -> F (in AD3; dbSNP:rs63750687)" FT /evidence="ECO:0000269|PubMed:24121961" FT /id="VAR_081257" FT VARIANT 381 FT /note="L -> V (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750687)" FT /evidence="ECO:0000269|PubMed:19797784, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081258" FT VARIANT 384 FT /note="G -> A (in AD3; results in reduced APP and Notch FT proteolysis; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750646)" FT /evidence="ECO:0000269|PubMed:16752394, FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634711" FT /id="VAR_006456" FT VARIANT 390 FT /note="S -> I (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750883)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341" FT /id="VAR_010128" FT VARIANT 392 FT /note="L -> V (in AD3; results in reduced APP and Notch FT proteolysis; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751416)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:8634712" FT /id="VAR_006457" FT VARIANT 394 FT /note="G -> V (in AD3; uncertain significance; abolishes FT protease activity with APP; dbSNP:rs63750929)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075276" FT VARIANT 396 FT /note="A -> T (in AD3; uncertain significance; decreased FT protease activity with APP; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_070026" FT VARIANT 405 FT /note="N -> S (in AD3; uncertain significance; decreased FT protease activity with APP; dbSNP:rs63751254)" FT /evidence="ECO:0000269|PubMed:10644793, FT ECO:0000269|PubMed:27930341" FT /id="VAR_010129" FT VARIANT 408 FT /note="I -> T (in AD3; dbSNP:rs906454643)" FT /evidence="ECO:0000269|PubMed:26549787" FT /id="VAR_075277" FT VARIANT 409 FT /note="A -> T (in AD3; uncertain significance; decreased FT protease activity with APP; dbSNP:rs63750227)" FT /evidence="ECO:0000269|PubMed:10533070, FT ECO:0000269|PubMed:27930341" FT /id="VAR_009213" FT VARIANT 410 FT /note="C -> Y (in AD3; results in reduced APP and Notch FT proteolysis; dbSNP:rs661)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634712, ECO:0000269|PubMed:9521423" FT /id="VAR_006458" FT VARIANT 417 FT /note="G -> A (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:30180983" FT /id="VAR_081259" FT VARIANT 418 FT /note="L -> F (in AD3; uncertain significance; nearly FT abolishes protease activity with APP; dbSNP:rs63751316)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075278" FT VARIANT 426 FT /note="A -> P (in AD3; uncertain significance; slightly FT decreased protease activity with APP; dbSNP:rs63751223)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:9521423" FT /id="VAR_006459" FT VARIANT 431 FT /note="A -> E (in AD3; decreased protease activity with FT APP; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750083)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:16628450, ECO:0000269|PubMed:16897084, FT ECO:0000269|PubMed:27930341, ECO:0000269|Ref.95" FT /id="VAR_025605" FT VARIANT 435 FT /note="L -> F (in AD3; with unusual amyloid cotton wool FT plaques; almost abolishes gamma-secretase activity; no FT endoproteolytic cleavage; no APP nor NOTCH1 processing; no FT detectable amyloid-beta; dbSNP:rs63750001)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:20460383, FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341" FT /id="VAR_075280" FT VARIANT 436 FT /note="P -> Q (in AD3; severe decrease of protease activity FT with APP; dbSNP:rs121917808)" FT /evidence="ECO:0000269|PubMed:22529981, FT ECO:0000269|PubMed:9831473" FT /id="VAR_006460" FT VARIANT 436 FT /note="P -> S (in AD3; partially abolishes gamma-secretase FT activity; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63749925)" FT /evidence="ECO:0000269|PubMed:10090481, FT ECO:0000269|PubMed:21248752, ECO:0000269|PubMed:27930341" FT /id="VAR_008141" FT VARIANT 439 FT /note="I -> V (in AD3; uncertain significance; no FT significant change of protease activity with APP; FT dbSNP:rs63750249)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075282" FT MUTAGEN 66..72 FT /note="Missing: No effect on interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 76..77 FT /note="KY->AA: No effect on interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 82..83 FT /note="VI->EE: Loss of interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 82 FT /note="V->K,E: Loss of interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 84..85 FT /note="ML->EE: Loss of interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 99 FT /note="T->A: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 105 FT /note="F->I: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 108 FT /note="R->Q: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 112 FT /note="Q->C: Formation of an artifactual disulfide bond FT with a substrate protein." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 113 FT /note="L->Q: Severe decrease of protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 117 FT /note="P->A: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 123 FT /note="E->K: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 131 FT /note="H->R: Severe decrease of protease activity with FT APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 136 FT /note="A->G: Decreased protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 143 FT /note="I->V: Increased amyloid-beta 42/amyloid-beta 40 FT ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 150 FT /note="L->P: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 165 FT /note="W->G: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 168 FT /note="I->T: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 176 FT /note="F->L: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 184 FT /note="E->G: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 202 FT /note="I->F: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 212 FT /note="S->Y: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 214 FT /note="H->D: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 219 FT /note="L->F: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 223 FT /note="Q->R: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 226 FT /note="L->F: Increases protease activity with APP." FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 230 FT /note="S->I: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 238 FT /note="I->M: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 239 FT /note="K->N: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 245 FT /note="T->P: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 248 FT /note="L->R: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 256 FT /note="Y->F: Alters gamma-secretase cleavage specificity. FT Increased production of amyloid-beta protein 42. No effect FT on enzymatic activity." FT /evidence="ECO:0000269|PubMed:15341515" FT MUTAGEN 256 FT /note="Y->S: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 257 FT /note="D->A: Loss of endoproteolytic cleavage. Severe FT decrease of protease activity with APP. Reduces production FT of amyloid-beta. Reduces production of NICD in NOTCH1 FT processing. Impaired ability to cleave Ephb2/CTF1." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:15341515, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:22529981" FT MUTAGEN 257 FT /note="D->E: Abolishes gamma-secretase activity. Reduces FT production of amyloid-beta in APP processing. Accumulation FT of full-length PS1. Loss of binding of transition state FT analog gamma-secretase inhibitor." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:15341515" FT MUTAGEN 272 FT /note="V->A: Increased amyloid-beta 42/amyloid-beta 40 FT ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 273 FT /note="E->A: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 278 FT /note="R->K: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 284 FT /note="P->S: No significant change of protease activity FT with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 286 FT /note="L->A,E,P,Q,R,W: Increases production of amyloid-beta FT in APP processing." FT /evidence="ECO:0000269|PubMed:10811883" FT MUTAGEN 286 FT /note="L->E,R: Reduces production of NICD in NOTCH1 FT processing." FT /evidence="ECO:0000269|PubMed:10811883" FT MUTAGEN 288..290 FT /note="Missing: Loss of NOTCH1 and APP C83 cleavage." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 291 FT /note="T->P: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 292 FT /note="M->D: Loss of endoproteolytic cleavage." FT /evidence="ECO:0000269|PubMed:10545183" FT MUTAGEN 310 FT /note="S->A: Abolishes PKA-mediated phosphorylation; no FT effect on caspase-mediated cleavage." FT /evidence="ECO:0000269|PubMed:14576165" FT MUTAGEN 345 FT /note="D->N: Abolishes caspase cleavage." FT /evidence="ECO:0000269|PubMed:9485372" FT MUTAGEN 346 FT /note="S->A: Abolishes PKC-mediated phosphorylation; no FT effect on PKA-mediated phosphorylation." FT /evidence="ECO:0000269|PubMed:14576165" FT MUTAGEN 346 FT /note="S->E: Inhibits caspase-mediated cleavage. Modulates FT progression of apoptosis." FT /evidence="ECO:0000269|PubMed:14576165" FT MUTAGEN 352 FT /note="R->C: Decreased protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 365 FT /note="S->A: Slightly increased protease activity with FT APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 373 FT /note="D->N: No effect on caspase cleavage." FT /evidence="ECO:0000269|PubMed:9485372" FT MUTAGEN 377..381 FT /note="Missing: Loss of NOTCH1 and APP C83 cleavage." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 377 FT /note="R->W: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 385 FT /note="D->A: Loss of endoproteolytic cleavage. Severe FT decrease of protease activity with APP. Reduces production FT of amyloid-beta. Loss of NOTCH1 cleavage. Disassembly of FT the N-cadherin/PS1 complex at the cell surface. Impairs FT CDH2 processing." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347, FT ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:22529981, FT ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, FT ECO:0000269|PubMed:9485372" FT MUTAGEN 385 FT /note="D->E: Abolishes gamma-secretase activity. Reduces FT production of amyloid-beta in APP processing. Accumulation FT of full-length PS1. Loss of binding of transition state FT analog gamma-secretase inhibitor." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347, FT ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:9485372" FT MUTAGEN 385 FT /note="D->N: No effect on caspase cleavage." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347, FT ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:9485372" FT MUTAGEN 386 FT /note="F->S: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 389 FT /note="Y->F: Alters gamma-secretase cleavage specificity. FT Increased production of amyloid-beta protein 42. No effect FT on enzymatic activity." FT /evidence="ECO:0000269|PubMed:15341515" FT MUTAGEN 391 FT /note="V->F: Decreased protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 412 FT /note="V->I: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 420 FT /note="L->R: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 424 FT /note="L->V: Increases protease activity with APP." FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 432..434 FT /note="Missing: Loss of NOTCH1 and APP C83 cleavage." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 432 FT /note="L->P: Loss of NOTCH1 and APP C83 cleavage." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 433 FT /note="P->A: No effect on endoproteolytic cleavage. No FT effect on APP nor NOTCH1 processing. Slightly increased FT amyloid-beta protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 433 FT /note="P->D,F,L,N,V: No endoproteolytic cleavage; no APP, FT nor NOTCH1 processing. No detectable amyloid-beta." FT /evidence="ECO:0000269|PubMed:16305624, FT ECO:0000269|PubMed:20460383" FT MUTAGEN 433 FT /note="P->G: Very little endoproteolysis. Little APP FT processing. No NOTCH1 processing. Very low levels amyloid- FT beta protein 40 and no detectable amyloid-beta protein 42." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 434 FT /note="A->C: Some loss of endoproteolytic cleavage. Some FT loss of APP and NOTCH1 processing. 6 to 13-fold increase in FT amyloid-beta protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 434 FT /note="A->D,I,L,V: No endoproteolytic cleavage. No APP nor FT NOTCH1 processing. No detectable amyloid-beta." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 434 FT /note="A->G: No effect on endoproteolytic cleavage. No FT effect on APP nor NOTCH1 processing. Reduced amyloid-beta FT protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 435 FT /note="L->A: No effect on endoproteolytic cleavage. No FT effect on APP processing. Impaired NOTCH1 processing. FT Greatly reduced amyloid-beta protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 435 FT /note="L->G: Greatly reduced endoproteolytic cleavage. Very FT little APP and NOTCH1 processing. Very low levels of FT amyloid-beta protein 40 and no detectable amyloid-beta FT protein 42." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 435 FT /note="L->I: No effect on endoproteolytic cleavage. No FT effect on APP nor NOTCH1 processing." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 435 FT /note="L->R: No endoproteolytic cleavage; no APP, nor FT NOTCH1 processing. No detectable amyloid-beta." FT /evidence="ECO:0000269|PubMed:20460383" FT MUTAGEN 435 FT /note="L->V: No effect on endoproteolytic cleavage. No FT effect on APP processing. Impaired NOTCH1 processing. Some FT increase in amyloid-beta protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 437 FT /note="I->V: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT CONFLICT 128 FT /note="R -> G (in Ref. 7; AAL16811)" FT /evidence="ECO:0000305" FT STRAND 77..80 FT /evidence="ECO:0007829|PDB:6LR4" FT HELIX 83..102 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 105..107 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 114..116 FT /evidence="ECO:0007829|PDB:8X52" FT STRAND 120..123 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 125..155 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 159..175 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 177..188 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 195..214 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 219..240 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 243..262 FT /evidence="ECO:0007829|PDB:8KCS" FT STRAND 263..266 FT /evidence="ECO:0007829|PDB:6IDF" FT HELIX 267..277 FT /evidence="ECO:0007829|PDB:8KCS" FT STRAND 278..280 FT /evidence="ECO:0007829|PDB:6IDF" FT TURN 284..286 FT /evidence="ECO:0007829|PDB:8KCU" FT STRAND 287..289 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 293..299 FT /evidence="ECO:0007829|PDB:2KR6" FT STRAND 341..345 FT /evidence="ECO:0007829|PDB:2KR6" FT HELIX 356..368 FT /evidence="ECO:0007829|PDB:2KR6" FT STRAND 380..382 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 383..398 FT /evidence="ECO:0007829|PDB:8KCS" FT STRAND 400..402 FT /evidence="ECO:0007829|PDB:8OQY" FT HELIX 403..428 FT /evidence="ECO:0007829|PDB:8KCS" FT STRAND 432..434 FT /evidence="ECO:0007829|PDB:6IDF" FT HELIX 435..451 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 454..463 FT /evidence="ECO:0007829|PDB:8KCS" SQ SEQUENCE 467 AA; 52668 MW; 5E0F451EF82BCF20 CRC64; MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL SNGRPQGNSR QVVEQDEEED EELTLKYGAK HVIMLFVPVT LCMVVVVATI KSVSFYTRKD GQLIYTPFTE DTETVGQRAL HSILNAAIMI SVIVVMTILL VVLYKYRCYK VIHAWLIISS LLLLFFFSFI YLGEVFKTYN VAVDYITVAL LIWNFGVVGM ISIHWKGPLR LQQAYLIMIS ALMALVFIKY LPEWTAWLIL AVISVYDLVA VLCPKGPLRM LVETAQERNE TLFPALIYSS TMVWLVNMAE GDPEAQRRVS KNSKYNAEST ERESQDTVAE NDDGGFSEEW EAQRDSHLGP HRSTPESRAA VQELSSSILA GEDPEERGVK LGLGDFIFYS VLVGKASATA SGDWNTTIAC FVAILIGLCL TLLLLAIFKK ALPALPISIT FGLVFYFATD YLVQPFMDQL AFHQFYI // ID QCR1_HUMAN Reviewed; 480 AA. AC P31930; B2R7R8; Q96DD2; DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot. DT 04-APR-2006, sequence version 3. DT 28-JAN-2026, entry version 228. DE RecName: Full=Cytochrome b-c1 complex subunit 1, mitochondrial; DE AltName: Full=Complex III subunit 1; DE AltName: Full=Core protein I; DE AltName: Full=Ubiquinol-cytochrome-c reductase complex core protein 1; DE Flags: Precursor; GN Name=UQCRC1; 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], AND VARIANT SER-301. RC TISSUE=Placenta; RX PubMed=8407948; DOI=10.1016/s0021-9258(19)36900-5; RA Hoffman G.G., Lee S., Christiano A.M., Chung-Honet L.C., Cheng W., RA Katchman S., Uitto J., Greenspan D.S.; RT "Complete coding sequence, intron/exon organization, and chromosomal RT location of the gene for the core I protein of human ubiquinol-cytochrome c RT reductase."; RL J. Biol. Chem. 268:21113-21119(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Fibroblast; RX PubMed=8069229; RA Islam M.M., Tanaka M., Suzuki H., Torii K., Hattori N., Ozawa T.; RT "A complete cDNA sequence for core I protein subunit of human ubiquinol- RT cytochrome c reductase."; RL Biochem. Mol. Biol. Int. 32:797-805(1994). RN [3] RP ERRATUM OF PUBMED:8069229. RX PubMed=7951059; RA Islam M.M., Tanaka M., Suzuki H., Torii K., Hattori N., Ozawa T.; RL Biochem. Mol. Biol. Int. 33:410-410(1994). RN [4] RP ERRATUM OF PUBMED:8069229. RX PubMed=7981668; RA Islam M.M., Tanaka M., Suzuki H., Torii K., Hattori N., Ozawa T.; RL Biochem. Mol. Biol. Int. 33:815-815(1994). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Subthalamic nucleus; 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]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Bone marrow; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP PROTEIN SEQUENCE OF 35-45. RC TISSUE=Liver; RX PubMed=8313870; DOI=10.1002/elps.11501401181; RA Hughes G.J., Frutiger S., Paquet N., Pasquali C., Sanchez J.-C., RA Tissot J.-D., Bairoch A., Appel R.D., Hochstrasser D.F.; RT "Human liver protein map: update 1993."; RL Electrophoresis 14:1216-1222(1993). RN [9] RP PROTEIN SEQUENCE OF 86-99; 214-225; 229-248; 397-415; 424-442; 448-470 AND RP 473-479, AND IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex; RA Lubec G., Vishwanath V., Chen W.-Q., Sun Y.; RL Submitted (DEC-2008) to UniProtKB. RN [10] RP PROTEIN SEQUENCE OF 143-165; 181-209 AND 397-415. RC TISSUE=Adipocyte; RX PubMed=15242332; DOI=10.1042/bj20040647; RA Aboulaich N., Vainonen J.P., Stralfors P., Vener A.V.; RT "Vectorial proteomics reveal targeting, phosphorylation and specific RT fragmentation of polymerase I and transcript release factor (PTRF) at the RT surface of caveolae in human adipocytes."; RL Biochem. J. 383:237-248(2004). RN [11] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-111, AND IDENTIFICATION BY MASS RP 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 [12] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [13] RP 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 CLEAVAGE OF TRANSIT PEPTIDE [LARGE SCALE ANALYSIS] AFTER SER-34, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [15] RP FUNCTION. RX PubMed=29243944; DOI=10.1080/15384101.2017.1417707; RA Fernandez-Vizarra E., Zeviani M.; RT "Mitochondrial complex III Rieske Fe-S protein processing and assembly."; RL Cell Cycle 17:681-687(2018). RN [16] RP INTERACTION WITH UQCC6. RX PubMed=32161263; DOI=10.1038/s41467-020-14999-2; RA Zhang S., Reljic B., Liang C., Kerouanton B., Francisco J.C., Peh J.H., RA Mary C., Jagannathan N.S., Olexiouk V., Tang C., Fidelito G., Nama S., RA Cheng R.K., Wee C.L., Wang L.C., Duek Roggli P., Sampath P., Lane L., RA Petretto E., Sobota R.M., Jesuthasan S., Tucker-Kellogg L., Reversade B., RA Menschaert G., Sun L., Stroud D.A., Ho L.; RT "Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory RT complex III assembly."; RL Nat. Commun. 11:1312-1312(2020). RN [17] RP STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), AND SUBUNIT. RX PubMed=28844695; DOI=10.1016/j.cell.2017.07.050; RA Guo R., Zong S., Wu M., Gu J., Yang M.; RT "Architecture of human mitochondrial respiratory megacomplex I2III2IV2."; RL Cell 170:1247-1257(2017). RN [18] RP VARIANT SER-301. RX PubMed=10453733; DOI=10.1007/s004390050988; RA Valnot I., Kassis J., Chretien D., de Lonlay P., Parfait B., Munnich A., RA Kachaner J., Rustin P., Roetig A.; RT "A mitochondrial cytochrome b mutation but no mutations of nuclearly RT encoded subunits in ubiquinol cytochrome c reductase (complex III) RT deficiency."; RL Hum. Genet. 104:460-466(1999). RN [19] RP INVOLVEMENT IN PKNPY, VARIANTS PKNPY LEU-311 AND SER-314, FUNCTION, AND RP TISSUE SPECIFICITY. RX PubMed=33141179; DOI=10.1093/brain/awaa279; RA Lin C.H., Tsai P.I., Lin H.Y., Hattori N., Funayama M., Jeon B., Sato K., RA Abe K., Mukai Y., Takahashi Y., Li Y., Nishioka K., Yoshino H., Daida K., RA Chen M.L., Cheng J., Huang C.Y., Tzeng S.R., Wu Y.S., Lai H.J., Tsai H.H., RA Yen R.F., Lee N.C., Lo W.C., Hung Y.C., Chan C.C., Ke Y.C., Chao C.C., RA Hsieh S.T., Farrer M., Wu R.M.; RT "Mitochondrial UQCRC1 mutations cause autosomal dominant parkinsonism with RT polyneuropathy."; RL Brain 143:3352-3373(2020). CC -!- FUNCTION: Component of the ubiquinol-cytochrome c oxidoreductase, a CC multisubunit transmembrane complex that is part of the mitochondrial CC electron transport chain which drives oxidative phosphorylation. The CC respiratory chain contains 3 multisubunit complexes succinate CC dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase CC (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase CC (complex IV, CIV), that cooperate to transfer electrons derived from CC NADH and succinate to molecular oxygen, creating an electrochemical CC gradient over the inner membrane that drives transmembrane transport CC and the ATP synthase. The cytochrome b-c1 complex catalyzes electron CC transfer from ubiquinol to cytochrome c, linking this redox reaction to CC translocation of protons across the mitochondrial inner membrane, with CC protons being carried across the membrane as hydrogens on the quinol. CC In the process called Q cycle, 2 protons are consumed from the matrix, CC 4 protons are released into the intermembrane space and 2 electrons are CC passed to cytochrome c (By similarity). The 2 core subunits UQCRC1/QCR1 CC and UQCRC2/QCR2 are homologous to the 2 mitochondrial-processing CC peptidase (MPP) subunits beta-MPP and alpha-MPP respectively, and they CC seem to have preserved their MPP processing properties (By similarity). CC May be involved in the in situ processing of UQCRFS1 into the mature CC Rieske protein and its mitochondrial targeting sequence (MTS)/subunit 9 CC when incorporated into complex III (Probable). Seems to play an CC important role in the maintenance of proper mitochondrial function in CC nigral dopaminergic neurons (PubMed:33141179). CC {ECO:0000250|UniProtKB:P07256, ECO:0000250|UniProtKB:P31800, CC ECO:0000269|PubMed:33141179, ECO:0000305|PubMed:29243944}. CC -!- SUBUNIT: Component of the ubiquinol-cytochrome c oxidoreductase CC (cytochrome b-c1 complex, complex III, CIII), a multisubunit enzyme CC composed of 11 subunits. The complex is composed of 3 respiratory CC subunits cytochrome b, cytochrome c1 and Rieske protein UQCRFS1, 2 core CC protein subunits UQCRC1/QCR1 and UQCRC2/QCR2, and 6 low-molecular CC weight protein subunits UQCRH/QCR6, UQCRB/QCR7, UQCRQ/QCR8, CC UQCR10/QCR9, UQCR11/QCR10 and subunit 9, the cleavage product of Rieske CC protein UQCRFS1 (By similarity). The complex exists as an obligatory CC dimer and forms supercomplexes (SCs) in the inner mitochondrial CC membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and CC cytochrome c oxidase (complex IV, CIV), resulting in different CC assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex CC MCI(2)III(2)IV(2)) (PubMed:28844695). Interacts with UQCC6 CC (PubMed:32161263). Interacts with STMP1 (By similarity). CC {ECO:0000250|UniProtKB:P31800, ECO:0000250|UniProtKB:Q9CZ13, CC ECO:0000269|PubMed:28844695, ECO:0000269|PubMed:32161263}. CC -!- INTERACTION: CC P31930; P52566: ARHGDIB; NbExp=3; IntAct=EBI-1052596, EBI-2806617; CC P31930; Q14457: BECN1; NbExp=3; IntAct=EBI-1052596, EBI-949378; CC P31930; Q9UFG5: C19orf25; NbExp=3; IntAct=EBI-1052596, EBI-741214; CC P31930; Q8WU43: C2orf15; NbExp=3; IntAct=EBI-1052596, EBI-12904676; CC P31930; Q8IV13: CCNJL; NbExp=3; IntAct=EBI-1052596, EBI-21668062; CC P31930; Q9Y6G5: COMMD10; NbExp=3; IntAct=EBI-1052596, EBI-1550310; CC P31930; P26641: EEF1G; NbExp=3; IntAct=EBI-1052596, EBI-351467; CC P31930; Q9UI10: EIF2B4; NbExp=3; IntAct=EBI-1052596, EBI-2340132; CC P31930; Q06547-2: GABPB1; NbExp=3; IntAct=EBI-1052596, EBI-618189; CC P31930; Q9HC44: GPBP1L1; NbExp=3; IntAct=EBI-1052596, EBI-746674; CC P31930; Q8N5Z5: KCTD17; NbExp=3; IntAct=EBI-1052596, EBI-743960; CC P31930; Q96JM7-2: L3MBTL3; NbExp=3; IntAct=EBI-1052596, EBI-11985629; CC P31930; Q8N108-16: MIER1; NbExp=3; IntAct=EBI-1052596, EBI-25830642; CC P31930; C9J082: NPHP1; NbExp=3; IntAct=EBI-1052596, EBI-25830675; CC P31930; Q9UHV9: PFDN2; NbExp=3; IntAct=EBI-1052596, EBI-359873; CC P31930; Q00169: PITPNA; NbExp=3; IntAct=EBI-1052596, EBI-1042490; CC P31930; O14744: PRMT5; NbExp=3; IntAct=EBI-1052596, EBI-351098; CC P31930; O95416: SOX14; NbExp=3; IntAct=EBI-1052596, EBI-9087806; CC P31930; Q9BUA3: SPINDOC; NbExp=3; IntAct=EBI-1052596, EBI-1773488; CC P31930; O43704: SULT1B1; NbExp=3; IntAct=EBI-1052596, EBI-10179062; CC P31930; O95947: TBX6; NbExp=3; IntAct=EBI-1052596, EBI-2824328; CC P31930; Q8WTV1: THAP3; NbExp=3; IntAct=EBI-1052596, EBI-17438286; CC P31930; Q9BZM4: ULBP3; NbExp=3; IntAct=EBI-1052596, EBI-1032551; CC P31930; P22695: UQCRC2; NbExp=4; IntAct=EBI-1052596, EBI-1051424; CC P31930; Q6ZMY6-2: WDR88; NbExp=3; IntAct=EBI-1052596, EBI-25857007; CC P31930; Q9UNY5: ZNF232; NbExp=3; IntAct=EBI-1052596, EBI-749023; CC P31930; Q96MN9-2: ZNF488; NbExp=3; IntAct=EBI-1052596, EBI-25831733; CC P31930; Q8N8E2: ZNF513; NbExp=3; IntAct=EBI-1052596, EBI-10279993; CC P31930; Q9P0T4: ZNF581; NbExp=3; IntAct=EBI-1052596, EBI-745520; CC P31930; Q9BRT8: ZNG1A; NbExp=3; IntAct=EBI-1052596, EBI-1054417; CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane CC {ECO:0000250|UniProtKB:P07256}; Peripheral membrane protein CC {ECO:0000250|UniProtKB:P07256}; Matrix side CC {ECO:0000250|UniProtKB:P07256}. CC -!- TISSUE SPECIFICITY: Expressed in brain, including substantia nigra, CC striatum, cortex and cerebellum, and in spinal cord, heart, kidney, CC liver and muscle. {ECO:0000269|PubMed:33141179}. CC -!- DISEASE: Parkinsonism with polyneuropathy (PKNPY) [MIM:619279]: An CC autosomal dominant disorder characterized by late-onset, levodopa- CC responsive parkinsonism with asymmetric tremor, rigidity and CC bradykinesia. Patients also manifest a sensorimotor polyneuropathy with CC variable degrees of distal legs and hands muscle atrophy and weakness, CC and absent deep tendon reflexes. {ECO:0000269|PubMed:33141179}. CC Note=The protein represented in this entry is involved in disease CC pathogenesis. CC -!- SIMILARITY: Belongs to the peptidase M16 family. UQCRC1/QCR1 subfamily. CC {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; L16842; AAA20046.1; -; mRNA. DR EMBL; D26485; BAA05495.1; -; mRNA. DR EMBL; AK313090; BAG35915.1; -; mRNA. DR EMBL; CH471055; EAW64898.1; -; Genomic_DNA. DR EMBL; BC009586; AAH09586.1; -; mRNA. DR CCDS; CCDS2774.1; -. DR PIR; A48043; A48043. DR RefSeq; NP_003356.2; NM_003365.2. DR RefSeq; XP_054203719.1; XM_054347744.1. DR PDB; 5XTE; EM; 3.40 A; L/Y=35-480. DR PDB; 5XTH; EM; 3.90 A; AL/AY=35-480. DR PDB; 5XTI; EM; 17.40 A; AL/AY=35-480. DR PDB; 9CG3; EM; 2.96 A; L/Y=1-480. DR PDBsum; 5XTE; -. DR PDBsum; 5XTH; -. DR PDBsum; 5XTI; -. DR PDBsum; 9CG3; -. DR AlphaFoldDB; P31930; -. DR EMDB; EMD-45567; -. DR SMR; P31930; -. DR BioGRID; 113230; 239. DR ComplexPortal; CPX-560; Mitochondrial respiratory chain complex III. DR FunCoup; P31930; 1647. DR IntAct; P31930; 113. DR MINT; P31930; -. DR STRING; 9606.ENSP00000203407; -. DR DrugBank; DB07763; (5S)-3-ANILINO-5-(2,4-DIFLUOROPHENYL)-5-METHYL-1,3-OXAZOLIDINE-2,4-DIONE. DR DrugBank; DB07778; (S)-famoxadone. DR DrugBank; DB04141; 2-Hexyloxy-6-Hydroxymethyl-Tetrahydro-Pyran-3,4,5-Triol. DR DrugBank; DB08453; 2-Nonyl-4-quinolinol 1-oxide. DR DrugBank; DB04799; 6-Hydroxy-5-undecyl-4,7-benzothiazoledione. DR DrugBank; DB07401; Azoxystrobin. DR DrugBank; DB08330; METHYL (2Z)-3-METHOXY-2-{2-[(E)-2-PHENYLVINYL]PHENYL}ACRYLATE. DR DrugBank; DB04741; Myxothiazol. DR DrugBank; DB08690; Ubiquinone Q2. DR MEROPS; M16.973; -. DR MEROPS; M16.981; -. DR GlyGen; P31930; 2 sites, 3 N-linked glycans (1 site), 1 O-linked glycan (1 site). DR iPTMnet; P31930; -. DR MetOSite; P31930; -. DR PhosphoSitePlus; P31930; -. DR SwissPalm; P31930; -. DR BioMuta; UQCRC1; -. DR DMDM; 92090651; -. DR OGP; P31930; -. DR REPRODUCTION-2DPAGE; IPI00013847; -. DR jPOST; P31930; -. DR MassIVE; P31930; -. DR PaxDb; 9606-ENSP00000203407; -. DR PeptideAtlas; P31930; -. DR ProteomicsDB; 54803; -. DR Pumba; P31930; -. DR Antibodypedia; 1257; 374 antibodies from 29 providers. DR DNASU; 7384; -. DR Ensembl; ENST00000203407.6; ENSP00000203407.5; ENSG00000010256.13. DR GeneID; 7384; -. DR KEGG; hsa:7384; -. DR MANE-Select; ENST00000203407.6; ENSP00000203407.5; NM_003365.3; NP_003356.2. DR UCSC; uc003cub.2; human. DR AGR; HGNC:12585; -. DR ClinPGx; PA37216; -. DR CTD; 7384; -. DR DisGeNET; 7384; -. DR GeneCards; UQCRC1; -. DR HGNC; HGNC:12585; UQCRC1. DR HPA; ENSG00000010256; Tissue enhanced (skeletal muscle, tongue). DR MalaCards; UQCRC1; -. DR MIM; 191328; gene. DR MIM; 619279; phenotype. DR OpenTargets; ENSG00000010256; -. DR VEuPathDB; HostDB:ENSG00000010256; -. DR eggNOG; KOG0960; Eukaryota. DR GeneTree; ENSGT00940000158931; -. DR HOGENOM; CLU_009902_4_0_1; -. DR InParanoid; P31930; -. DR OMA; HFAQGEW; -. DR OrthoDB; 10251424at2759; -. DR PAN-GO; P31930; 1 GO annotation based on evolutionary models. DR PhylomeDB; P31930; -. DR BioCyc; MetaCyc:HS00277-MONOMER; -. DR PathwayCommons; P31930; -. DR Reactome; R-HSA-611105; Respiratory electron transport. DR Reactome; R-HSA-9865881; Complex III assembly. DR SignaLink; P31930; -. DR SIGNOR; P31930; -. DR Agora; ENSG00000010256; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 7384; 417 hits in 1176 CRISPR screens. DR CD-CODE; 91857CE7; Nucleolus. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; UQCRC1; human. DR GeneWiki; UQCRC1; -. DR GenomeRNAi; 7384; -. DR Pharos; P31930; Tbio. DR PRO; PR:P31930; -. DR Proteomes; UP000005640; Chromosome 3. DR RNAct; P31930; protein. DR Bgee; ENSG00000010256; Expressed in apex of heart and 210 other cell types or tissues. DR ExpressionAtlas; P31930; baseline and differential. DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:ComplexPortal. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0098803; C:respiratory chain complex; TAS:ProtInc. DR GO; GO:0045275; C:respiratory chain complex III; IPI:ComplexPortal. DR GO; GO:0046872; F:metal ion binding; IEA:InterPro. DR GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl. DR GO; GO:0008121; F:quinol-cytochrome-c reductase activity; TAS:ProtInc. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0009060; P:aerobic respiration; TAS:ProtInc. DR GO; GO:0045333; P:cellular respiration; NAS:ComplexPortal. DR GO; GO:0006122; P:mitochondrial electron transport, ubiquinol to cytochrome c; NAS:ComplexPortal. DR GO; GO:0006119; P:oxidative phosphorylation; TAS:ProtInc. DR GO; GO:0014823; P:response to activity; IEA:Ensembl. DR GO; GO:0043279; P:response to alkaloid; IEA:Ensembl. DR FunFam; 3.30.830.10:FF:000016; Cytochrome b-c1 complex subunit 1, mitochondrial; 1. DR FunFam; 3.30.830.10:FF:000001; Mitochondrial-processing peptidase subunit beta, mitochondrial; 1. DR Gene3D; 3.30.830.10; Metalloenzyme, LuxS/M16 peptidase-like; 2. DR InterPro; IPR011249; Metalloenz_LuxS/M16. DR InterPro; IPR050361; MPP/UQCRC_Complex. DR InterPro; IPR011765; Pept_M16_N. DR InterPro; IPR007863; Peptidase_M16_C. DR PANTHER; PTHR11851:SF116; CYTOCHROME B-C1 COMPLEX SUBUNIT 1, MITOCHONDRIAL; 1. DR PANTHER; PTHR11851; METALLOPROTEASE; 1. DR Pfam; PF00675; Peptidase_M16; 1. DR Pfam; PF05193; Peptidase_M16_C; 1. DR SUPFAM; SSF63411; LuxS/MPP-like metallohydrolase; 2. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Direct protein sequencing; Disease variant; KW Electron transport; Membrane; Mitochondrion; Mitochondrion inner membrane; KW Neuropathy; Parkinsonism; Phosphoprotein; Proteomics identification; KW Reference proteome; Respiratory chain; Transit peptide; Transport. FT TRANSIT 1..34 FT /note="Mitochondrion" FT /evidence="ECO:0000269|PubMed:8313870, FT ECO:0007744|PubMed:25944712" FT CHAIN 35..480 FT /note="Cytochrome b-c1 complex subunit 1, mitochondrial" FT /id="PRO_0000026786" FT MOD_RES 111 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 138 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q9CZ13" FT MOD_RES 163 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:Q9CZ13" FT MOD_RES 163 FT /note="N6-succinyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:Q9CZ13" FT MOD_RES 212 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q68FY0" FT MOD_RES 248 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q9CZ13" FT VARIANT 215 FT /note="D -> H (in dbSNP:rs17080284)" FT /id="VAR_034581" FT VARIANT 301 FT /note="N -> S (in dbSNP:rs144710790)" FT /evidence="ECO:0000269|PubMed:10453733, FT ECO:0000269|PubMed:8407948" FT /id="VAR_013629" FT VARIANT 311 FT /note="I -> L (in PKNPY; dbSNP:rs2107843274)" FT /evidence="ECO:0000269|PubMed:33141179" FT /id="VAR_085428" FT VARIANT 314 FT /note="Y -> S (in PKNPY; dbSNP:rs780978963)" FT /evidence="ECO:0000269|PubMed:33141179" FT /id="VAR_085429" FT HELIX 38..44 FT /evidence="ECO:0007829|PDB:5XTE" FT STRAND 67..69 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 84..86 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 89..95 FT /evidence="ECO:0007829|PDB:5XTE" FT STRAND 96..99 FT /evidence="ECO:0007829|PDB:5XTE" FT STRAND 102..104 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 106..116 FT /evidence="ECO:0007829|PDB:5XTE" FT STRAND 121..124 FT /evidence="ECO:0007829|PDB:5XTE" FT STRAND 129..132 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 137..139 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 140..150 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 158..175 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 181..192 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 196..198 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 205..208 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 213..222 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 239..250 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 258..260 FT /evidence="ECO:0007829|PDB:5XTE" FT STRAND 285..294 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 300..311 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 327..332 FT /evidence="ECO:0007829|PDB:5XTE" FT TURN 333..336 FT /evidence="ECO:0007829|PDB:5XTE" FT STRAND 339..347 FT /evidence="ECO:0007829|PDB:5XTE" FT STRAND 349..360 FT /evidence="ECO:0007829|PDB:5XTE" FT TURN 362..364 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 365..380 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 385..401 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 406..419 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 426..434 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 438..448 FT /evidence="ECO:0007829|PDB:5XTE" FT TURN 449..451 FT /evidence="ECO:0007829|PDB:5XTE" FT STRAND 455..461 FT /evidence="ECO:0007829|PDB:5XTE" FT STRAND 463..465 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 468..472 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 473..475 FT /evidence="ECO:0007829|PDB:5XTE" SQ SEQUENCE 480 AA; 52646 MW; E76B082166CAF48F CRC64; MAASVVCRAA TAGAQVLLRA RRSPALLRTP ALRSTATFAQ ALQFVPETQV SLLDNGLRVA SEQSSQPTCT VGVWIDVGSR FETEKNNGAG YFLEHLAFKG TKNRPGSALE KEVESMGAHL NAYSTREHTA YYIKALSKDL PKAVELLGDI VQNCSLEDSQ IEKERDVILR EMQENDASMR DVVFNYLHAT AFQGTPLAQA VEGPSENVRK LSRADLTEYL STHYKAPRMV LAAAGGVEHQ QLLDLAQKHL GGIPWTYAED AVPTLTPCRF TGSEIRHRDD ALPFAHVAIA VEGPGWASPD NVALQVANAI IGHYDCTYGG GVHLSSPLAS GAVANKLCQS FQTFSICYAE TGLLGAHFVC DRMKIDDMMF VLQGQWMRLC TSATESEVAR GKNILRNALV SHLDGTTPVC EDIGRSLLTY GRRIPLAEWE SRIAEVDASV VREICSKYIY DQCPAVAGYG PIEQLPDYNR IRSGMFWLRF // ID UCHL1_HUMAN Reviewed; 223 AA. AC P09936; Q4W5K6; Q71UM0; DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1990, sequence version 2. DT 28-JAN-2026, entry version 248. DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase isozyme L1; DE Short=UCH-L1; DE EC=3.4.19.12 {ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:16475834, ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}; DE AltName: Full=Neuron cytoplasmic protein 9.5; DE AltName: Full=PGP 9.5; DE Short=PGP9.5; DE AltName: Full=Ubiquitin thioesterase L1; DE Flags: Precursor; GN Name=UCHL1; 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 [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 [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 (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Lung, and Muscle; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-15. RX PubMed=2163617; DOI=10.1042/bj2680521; RA Day I.N.M., Hinks L.J., Thompson R.J.; RT "The structure of the human gene encoding protein gene product 9.5 RT (PGP9.5), a neuron-specific ubiquitin C-terminal hydrolase."; RL Biochem. J. 268:521-524(1990). RN [5] RP PROTEIN SEQUENCE OF 1-15 AND 214-221, SUSCEPTIBILITY TO OXIDATION, RP IDENTIFICATION BY MASS SPECTROMETRY, AND TISSUE SPECIFICITY. RX PubMed=14722078; DOI=10.1074/jbc.m314124200; RA Choi J., Levey A.I., Weintraub S.T., Rees H.D., Gearing M., Chin L.-S., RA Li L.; RT "Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal RT hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's RT diseases."; RL J. Biol. Chem. 279:13256-13264(2004). RN [6] RP PROTEIN SEQUENCE OF 1-15; 20-27; 66-78; 84-129; 136-195 AND 214-221, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex; RA Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y.; RL Submitted (DEC-2008) to UniProtKB. RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 7-223, AND PARTIAL PROTEIN SEQUENCE. RX PubMed=2947814; DOI=10.1016/0014-5793(87)81327-3; RA Day I.N.M., Thompson R.J.; RT "Molecular cloning of cDNA coding for human PGP 9.5 protein. A novel RT cytoplasmic marker for neurones and neuroendocrine cells."; RL FEBS Lett. 210:157-160(1987). RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 16-223, FUNCTION, CATALYTIC ACTIVITY, RP BIOPHYSICOCHEMICAL PROPERTIES, VARIANT PARK5 MET-93, AND CHARACTERIZATION RP OF VARIANT PARK5 MET-93. RX PubMed=9774100; DOI=10.1038/26652; RA Leroy E., Boyer R., Auburger G., Leube B., Ulm G., Mezey E., Harta G., RA Brownstein M.J., Jonnalagada S., Chernova T., Dehejia A., Lavedan C., RA Gasser T., Steinbach P.J., Wilkinson K.D., Polymeropoulos M.H.; RT "The ubiquitin pathway in Parkinson's disease."; RL Nature 395:451-452(1998). RN [9] RP PROTEIN SEQUENCE OF 20-25; 79-81; 106-121 AND 134-151. RX PubMed=1849484; DOI=10.1016/0014-5793(91)80300-r; RA Honore B., Rasmussen H.H., Vandekerckhove J., Celis J.E.; RT "Neuronal protein gene product 9.5 (IEF SSP 6104) is expressed in cultured RT human MRC-5 fibroblasts of normal origin and is strongly down-regulated in RT their SV40 transformed counterparts."; RL FEBS Lett. 280:235-240(1991). RN [10] RP PROTEIN SEQUENCE OF 20-25; 79-91; 106-123 AND 136-151. RX PubMed=1286667; DOI=10.1002/elps.11501301199; RA Rasmussen H.H., van Damme J., Puype M., Gesser B., Celis J.E., RA Vandekerckhove J.; RT "Microsequences of 145 proteins recorded in the two-dimensional gel protein RT database of normal human epidermal keratinocytes."; RL Electrophoresis 13:960-969(1992). RN [11] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, MUTAGENESIS OF GLN-73; CYS-90; RP HIS-97; HIS-161 AND ASP-176, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=8639624; DOI=10.1021/bi960099f; RA Larsen C.N., Price J.S., Wilkinson K.D.; RT "Substrate binding and catalysis by ubiquitin C-terminal hydrolases: RT identification of two active site residues."; RL Biochemistry 35:6735-6744(1996). RN [12] RP TISSUE SPECIFICITY. RX PubMed=9790970; DOI=10.1006/bbrc.1998.9532; RA Wada H., Kito K., Caskey L.S., Yeh E.T.H., Kamitani T.; RT "Cleavage of the C-terminus of NEDD8 by UCH-L3."; RL Biochem. Biophys. Res. Commun. 251:688-692(1998). RN [13] RP FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANT PARK5 MET-93, AND RP CHARACTERIZATION OF VARIANT TYR-18. RX PubMed=12408865; DOI=10.1016/s0092-8674(02)01012-7; RA Liu Y., Fallon L., Lashuel H.A., Liu Z., Lansbury P.T. Jr.; RT "The UCH-L1 gene encodes two opposing enzymatic activities that affect RT alpha-synuclein degradation and Parkinson's disease susceptibility."; RL Cell 111:209-218(2002). RN [14] RP INTERACTION WITH COPS5. RX PubMed=12082530; DOI=10.1038/sj.onc.1205390; RA Caballero O.L., Resto V., Patturajan M., Meerzaman D., Guo M.Z., Engles J., RA Yochem R., Ratovitski E., Sidransky D., Jen J.; RT "Interaction and colocalization of PGP9.5 with JAB1 and p27(Kip1)."; RL Oncogene 21:3003-3010(2002). RN [15] RP CATALYTIC ACTIVITY, AND ACTIVE SITE. RX PubMed=16475834; DOI=10.1021/bi052135t; RA Case A., Stein R.L.; RT "Mechanistic studies of ubiquitin C-terminal hydrolase L1."; RL Biochemistry 45:2443-2452(2006). RN [16] RP SUBCELLULAR LOCATION, AND ISOPRENYLATION AT CYS-220. RX PubMed=19261853; DOI=10.1073/pnas.0806474106; RA Liu Z., Meray R.K., Grammatopoulos T.N., Fredenburg R.A., Cookson M.R., RA Liu Y., Logan T., Lansbury P.T. Jr.; RT "Membrane-associated farnesylated UCH-L1 promotes alpha-synuclein RT neurotoxicity and is a therapeutic target for Parkinson's disease."; RL Proc. Natl. Acad. Sci. U.S.A. 106:4635-4640(2009). RN [17] 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 [18] 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 [19] RP FUNCTION. RX PubMed=22212137; DOI=10.1111/j.1471-4159.2011.07644.x; RA Zhang M., Deng Y., Luo Y., Zhang S., Zou H., Cai F., Wada K., Song W.; RT "Control of BACE1 degradation and APP processing by ubiquitin carboxyl- RT terminal hydrolase L1."; RL J. Neurochem. 120:1129-1138(2012). RN [20] RP FUNCTION, CATALYTIC ACTIVITY, VARIANTS SPG79B ALA-7 AND MET-93, RP CHARACTERIZATION OF VARIANT SPG79B ALA-7, AND MUTAGENESIS OF CYS-90. RX PubMed=23359680; DOI=10.1073/pnas.1222732110; RA Bilguvar K., Tyagi N.K., Ozkara C., Tuysuz B., Bakircioglu M., Choi M., RA Delil S., Caglayan A.O., Baranoski J.F., Erturk O., Yalcinkaya C., RA Karacorlu M., Dincer A., Johnson M.H., Mane S., Chandra S.S., Louvi A., RA Boggon T.J., Lifton R.P., Horwich A.L., Gunel M.; RT "Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads RT to early-onset progressive neurodegeneration."; RL Proc. Natl. Acad. Sci. U.S.A. 110:3489-3494(2013). RN [21] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF CYS-90. RX PubMed=25615526; DOI=10.1038/ncomms7153; RA Goto Y., Zeng L., Yeom C.J., Zhu Y., Morinibu A., Shinomiya K., RA Kobayashi M., Hirota K., Itasaka S., Yoshimura M., Tanimoto K., Torii M., RA Sowa T., Menju T., Sonobe M., Kakeya H., Toi M., Date H., Hammond E.M., RA Hiraoka M., Harada H.; RT "UCHL1 provides diagnostic and antimetastatic strategies due to its RT deubiquitinating effect on HIF-1alpha."; RL Nat. Commun. 6:6153-6153(2015). RN [22] RP IDENTIFICATION BY MASS SPECTROMETRY (ISOFORMS 2 AND 3), AND ACETYLATION AT RP MET-1 (ISOFORMS 1; 2 AND 3). RX PubMed=37316325; DOI=10.26508/lsa.202301972; RA Bogaert A., Fijalkowska D., Staes A., Van de Steene T., Vuylsteke M., RA Stadler C., Eyckerman S., Spirohn K., Hao T., Calderwood M.A., Gevaert K.; RT "N-terminal proteoforms may engage in different protein complexes."; RL Life. Sci Alliance 6:0-0(2023). RN [23] RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS), AND SUBUNIT. RX PubMed=16537382; DOI=10.1073/pnas.0510403103; RA Das C., Hoang Q.Q., Kreinbring C.A., Luchansky S.J., Meray R.K., Ray S.S., RA Lansbury P.T., Ringe D., Petsko G.A.; RT "Structural basis for conformational plasticity of the Parkinson's disease- RT associated ubiquitin hydrolase UCH-L1."; RL Proc. Natl. Acad. Sci. U.S.A. 103:4675-4680(2006). RN [24] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF VARIANTS TYR-18 AND MET-93 IN RP COMPLEX WITH UBIQUITIN, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF RP CYS-90 AND PHE-204. RX PubMed=20439756; DOI=10.1073/pnas.0910870107; RA Boudreaux D.A., Maiti T.K., Davies C.W., Das C.; RT "Ubiquitin vinyl methyl ester binding orients the misaligned active site of RT the ubiquitin hydrolase UCHL1 into productive conformation."; RL Proc. Natl. Acad. Sci. U.S.A. 107:9117-9122(2010). RN [25] RP CHARACTERIZATION OF VARIANT PARK5 MET-93, CHARACTERIZATION OF VARIANT RP TYR-18, MUTAGENESIS OF CYS-90, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL RP PROPERTIES. RX PubMed=12705903; DOI=10.1016/s0006-291x(03)00555-2; RA Nishikawa K., Li H., Kawamura R., Osaka H., Wang Y.-L., Hara Y., RA Hirokawa T., Manago Y., Amano T., Noda M., Aoki S., Wada K.; RT "Alterations of structure and hydrolase activity of parkinsonism-associated RT human ubiquitin carboxyl-terminal hydrolase L1 variants."; RL Biochem. Biophys. Res. Commun. 304:176-183(2003). RN [26] RP VARIANT MET-93. RX PubMed=10454131; DOI=10.1016/s0304-3940(99)00465-6; RA Harhangi B.S., Farrer M.J., Lincoln S., Bonifati V., Meco G., RA De Michele G., Brice A., Durr A., Martinez M., Gasser T., Bereznai B., RA Vaughan J.R., Wood N.W., Hardy J., Oostra B.A., Breteler M.M.; RT "The Ile93Met mutation in the ubiquitin carboxy-terminal-hydrolase-L1 gene RT is not observed in European cases with familial Parkinson's disease."; RL Neurosci. Lett. 270:1-4(1999). RN [27] RP VARIANT TYR-18. RX PubMed=10203348; DOI=10.1097/00001756-199902050-00040; RA Lincoln S., Vaughan J., Wood N., Baker M., Adamson J., Gwinn-Hardy K., RA Lynch T., Hardy J., Farrer M.; RT "Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal RT hydrolase gene in familial Parkinson's disease."; RL NeuroReport 10:427-429(1999). RN [28] RP VARIANT TYR-18. RX PubMed=11027850; DOI=10.1016/s0304-3940(00)01510-x; RA Mellick G.D., Silburn P.A.; RT "The ubiquitin carboxy-terminal hydrolase-L1 gene S18Y polymorphism does RT not confer protection against idiopathic Parkinson's disease."; RL Neurosci. Lett. 293:127-130(2000). RN [29] RP VARIANT TYR-18. RX PubMed=15048890; DOI=10.1002/ana.20017; RG UCHL1 global genetics consortium; RA Maraganore D.M., Lesnick T.G., Elbaz A., Chartier-Harlin M.-C., Gasser T., RA Krueger R., Hattori N., Mellick G.D., Quattrone A., Satoh J., Toda T., RA Wang J., Ioannidis J.P.A., de Andrade M., Rocca W.A.; RT "UCHL1 is a Parkinson's disease susceptibility gene."; RL Ann. Neurol. 55:512-521(2004). RN [30] RP ERRATUM OF PUBMED:15048890. RG UCHL1 global genetics consortium; RA Maraganore D.M., Lesnick T.G., Elbaz A., Chartier-Harlin M.-C., Gasser T., RA Krueger R., Hattori N., Mellick G.D., Quattrone A., Satoh J., Toda T., RA Wang J., Ioannidis J.P.A., de Andrade M., Rocca W.A.; RL Ann. Neurol. 55:899-899(2004). RN [31] RP VARIANT TYR-18, AND LACK OF ASSOCIATION OF VARIANT TYR-18 WITH PARKINSON RP DISEASE. RX PubMed=16450370; DOI=10.1002/ana.20757; RA Healy D.G., Abou-Sleiman P.M., Casas J.P., Ahmadi K.R., Lynch T., RA Gandhi S., Muqit M.M., Foltynie T., Barker R., Bhatia K.P., Quinn N.P., RA Lees A.J., Gibson J.M., Holton J.L., Revesz T., Goldstein D.B., Wood N.W.; RT "UCHL-1 is not a Parkinson's disease susceptibility gene."; RL Ann. Neurol. 59:627-633(2006). RN [32] RP CHARACTERIZATION OF VARIANT TYR-18, AND ANTIOXIDANT FUNCTION IN NEURONAL RP CELLS. RX PubMed=18411255; DOI=10.1093/hmg/ddn115; RA Kyratzi E., Pavlaki M., Stefanis L.; RT "The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to RT neuronal cells."; RL Hum. Mol. Genet. 17:2160-2171(2008). RN [33] RP VARIANT TYR-18. RX PubMed=21268678; DOI=10.3109/13816810.2010.544360; RA Rudolph T., Sjolander A., Palmer M.S., Minthon L., Wallin A., Andreasen N., RA Tasa G., Juronen E., Blennow K., Zetterberg H., Zetterberg M.; RT "Ubiquitin carboxyl-terminal esterase L1 (UCHL1) S18Y polymorphism in RT patients with cataracts."; RL Ophthalmic Genet. 32:75-79(2011). RN [34] RP VARIANTS SPG79B GLN-178 AND ASP-216, AND CHARACTERIZATION OF VARIANTS RP SPG79B GLN-178 AND ASP-216. RX PubMed=28007905; DOI=10.1093/hmg/ddw391; RA Rydning S.L., Backe P.H., Sousa M.M., Iqbal Z., Oeye A.M., Sheng Y., RA Yang M., Lin X., Slupphaug G., Nordenmark T.H., Vigeland M.D., Bjoeraas M., RA Tallaksen C.M., Selmer K.K.; RT "Novel UCHL1 mutations reveal new insights into ubiquitin processing."; RL Hum. Mol. Genet. 26:1031-1040(2017). RN [35] RP VARIANTS SPG79A 2-GLN--ALA-223 DEL; 25-GLN--ALA-223 DEL; LEU-52 INS; RP 178-ARG--ALA-223 DEL AND 211-GLU--ALA-223 DEL, AND INVOLVEMENT IN SPG79A. RX PubMed=35986737; DOI=10.1016/j.gim.2022.07.006; RG Genomics England Research Consortium; RA Park J., Tucci A., Cipriani V., Demidov G., Rocca C., Senderek J., RA Butryn M., Velic A., Lam T., Galanaki E., Cali E., Vestito L., RA Maroofian R., Deininger N., Rautenberg M., Admard J., Hahn G.A., RA Bartels C., van Os N.J.H., Horvath R., Chinnery P.F., Tiet M.Y., RA Hewamadduma C., Hadjivassiliou M., Tofaris G.K., Wood N.W., Hayer S.N., RA Bender F., Menden B., Cordts I., Klein K., Nguyen H.P., Krauss J.K., RA Blahak C., Strom T.M., Sturm M., van de Warrenburg B., Lerche H., Macek B., RA Synofzik M., Ossowski S., Timmann D., Wolf M.E., Smedley D., Riess O., RA Schoels L., Houlden H., Haack T.B., Hengel H.; RT "Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative RT disorder with spasticity, ataxia, neuropathy, and optic atrophy."; RL Genet. Med. 24:2079-2090(2022). CC -!- FUNCTION: Deubiquitinase that plays a role in the regulation of several CC processes such as maintenance of synaptic function, cardiac function, CC inflammatory response or osteoclastogenesis (PubMed:22212137, CC PubMed:23359680). Abrogates the ubiquitination of multiple proteins CC including WWTR1/TAZ, EGFR, HIF1A and beta-site amyloid precursor CC protein cleaving enzyme 1/BACE1 (PubMed:22212137, PubMed:25615526). In CC addition, recognizes and hydrolyzes a peptide bond at the C-terminal CC glycine of ubiquitin to maintain a stable pool of monoubiquitin that is CC a key requirement for the ubiquitin-proteasome and the autophagy- CC lysosome pathways (PubMed:12408865, PubMed:8639624, PubMed:9774100). CC Regulates amyloid precursor protein/APP processing by promoting BACE1 CC degradation resulting in decreased amyloid beta production CC (PubMed:22212137). Plays a role in the immune response by regulating CC the ability of MHC I molecules to reach cross-presentation compartments CC competent for generating Ag-MHC I complexes (By similarity). Mediates CC the 'Lys-48'-linked deubiquitination of the transcriptional coactivator CC WWTR1/TAZ leading to its stabilization and inhibition of CC osteoclastogenesis (By similarity). Deubiquitinates and stabilizes CC epidermal growth factor receptor EGFR to prevent its degradation and to CC activate its downstream mediators (By similarity). Modulates oxidative CC activity in skeletal muscle by regulating key mitochondrial oxidative CC proteins (By similarity). Enhances the activity of hypoxia-inducible CC factor 1-alpha/HIF1A by abrogateing its VHL E3 ligase-mediated CC ubiquitination and consequently inhibiting its degradation CC (PubMed:25615526). {ECO:0000250|UniProtKB:Q9R0P9, CC ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:22212137, CC ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:25615526, CC ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide CC and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76- CC residue protein attached to proteins as an intracellular targeting CC signal).; EC=3.4.19.12; Evidence={ECO:0000269|PubMed:12408865, CC ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:16475834, CC ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680, CC ECO:0000269|PubMed:25615526, ECO:0000269|PubMed:8639624, CC ECO:0000269|PubMed:9774100}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=122 nM for Ub-AMC {ECO:0000269|PubMed:12705903, CC ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}; CC KM=1.20 uM for ubiquitin ethyl ester {ECO:0000269|PubMed:12705903, CC ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}; CC Vmax=0.47 umol/min/mg enzyme toward Ub-AMC CC {ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:8639624, CC ECO:0000269|PubMed:9774100}; CC Vmax=25 umol/min/mg enzyme toward ubiquitin ethyl ester CC {ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:8639624, CC ECO:0000269|PubMed:9774100}; CC -!- SUBUNIT: Monomer. Homodimer. Interacts with SNCA (By similarity). CC Interacts with COPS5. {ECO:0000250, ECO:0000269|PubMed:12082530, CC ECO:0000269|PubMed:16537382, ECO:0000269|PubMed:20439756}. CC -!- INTERACTION: CC P09936; P63010-2: AP2B1; NbExp=3; IntAct=EBI-714860, EBI-11529439; CC P09936; P05067: APP; NbExp=5; IntAct=EBI-714860, EBI-77613; CC P09936; P05067-2: APP; NbExp=3; IntAct=EBI-714860, EBI-17264467; CC P09936; Q8N6T3-3: ARFGAP1; NbExp=3; IntAct=EBI-714860, EBI-10694449; CC P09936; P18847: ATF3; NbExp=3; IntAct=EBI-714860, EBI-712767; CC P09936; Q9H1Y0: ATG5; NbExp=4; IntAct=EBI-714860, EBI-1047414; CC P09936; O15392: BIRC5; NbExp=3; IntAct=EBI-714860, EBI-518823; CC P09936; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-714860, EBI-2837444; CC P09936; P83916: CBX1; NbExp=4; IntAct=EBI-714860, EBI-78129; CC P09936; P11802: CDK4; NbExp=4; IntAct=EBI-714860, EBI-295644; CC P09936; Q00535: CDK5; NbExp=2; IntAct=EBI-714860, EBI-1041567; CC P09936; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-714860, EBI-350590; CC P09936; Q92905: COPS5; NbExp=3; IntAct=EBI-714860, EBI-594661; CC P09936; P00533: EGFR; NbExp=3; IntAct=EBI-714860, EBI-297353; CC P09936; O60739: EIF1B; NbExp=4; IntAct=EBI-714860, EBI-1043343; CC P09936; Q8TC29: ENKUR; NbExp=3; IntAct=EBI-714860, EBI-9246952; CC P09936; Q9UI08-2: EVL; NbExp=3; IntAct=EBI-714860, EBI-6448852; CC P09936; Q8WVV9-3: HNRNPLL; NbExp=3; IntAct=EBI-714860, EBI-25845242; CC P09936; Q14164: IKBKE; NbExp=4; IntAct=EBI-714860, EBI-307369; CC P09936; Q6DN90-2: IQSEC1; NbExp=3; IntAct=EBI-714860, EBI-21911304; CC P09936; Q96JM7-2: L3MBTL3; NbExp=3; IntAct=EBI-714860, EBI-11985629; CC P09936; P13473-2: LAMP2; NbExp=3; IntAct=EBI-714860, EBI-21591415; CC P09936; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-714860, EBI-1108377; CC P09936; O95777: LSM8; NbExp=3; IntAct=EBI-714860, EBI-347779; CC P09936; A4FUJ8: MKL1; NbExp=3; IntAct=EBI-714860, EBI-21250407; CC P09936; Q15843: NEDD8; NbExp=4; IntAct=EBI-714860, EBI-716247; CC P09936; O15381-5: NVL; NbExp=3; IntAct=EBI-714860, EBI-18577082; CC P09936; Q9BR81: PCDHGC3; NbExp=3; IntAct=EBI-714860, EBI-22012354; CC P09936; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-714860, EBI-716063; CC P09936; P62826: RAN; NbExp=3; IntAct=EBI-714860, EBI-286642; CC P09936; Q8TAI7: RHEBL1; NbExp=3; IntAct=EBI-714860, EBI-746555; CC P09936; Q9ULX5: RNF112; NbExp=3; IntAct=EBI-714860, EBI-25829984; CC P09936; Q15554-4: TERF2; NbExp=3; IntAct=EBI-714860, EBI-25840535; CC P09936; Q9NYB0: TERF2IP; NbExp=2; IntAct=EBI-714860, EBI-750109; CC P09936; P04637: TP53; NbExp=3; IntAct=EBI-714860, EBI-366083; CC P09936; Q9Y4K3: TRAF6; NbExp=4; IntAct=EBI-714860, EBI-359276; CC P09936; P19474: TRIM21; NbExp=3; IntAct=EBI-714860, EBI-81290; CC P09936; Q9BSL1: UBAC1; NbExp=3; IntAct=EBI-714860, EBI-749370; CC P09936; Q7KZS0: UBE2I; NbExp=3; IntAct=EBI-714860, EBI-10180829; CC P09936; P61086: UBE2K; NbExp=3; IntAct=EBI-714860, EBI-473850; CC P09936; Q9UK80: USP21; NbExp=4; IntAct=EBI-714860, EBI-373242; CC P09936; Q86WB0-2: ZC3HC1; NbExp=3; IntAct=EBI-714860, EBI-25894765; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19261853}. CC Endoplasmic reticulum membrane {ECO:0000269|PubMed:19261853}; Lipid- CC anchor {ECO:0000269|PubMed:19261853}. Note=About 30% of total UCHL1 is CC associated with membranes in brain. Localizes near and/or within CC mitochondria to potentially interact with mitochondrial proteins. CC {ECO:0000250|UniProtKB:Q9R0P9}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative initiation; Named isoforms=3; CC Name=1; CC IsoId=P09936-1; Sequence=Displayed; CC Name=2; CC IsoId=P09936-2; Sequence=VSP_062524; CC Name=3; CC IsoId=P09936-3; Sequence=VSP_062523; CC -!- TISSUE SPECIFICITY: Found in neuronal cell bodies and processes CC throughout the neocortex (at protein level). Expressed in neurons and CC cells of the diffuse neuroendocrine system and their tumors. Weakly CC expressed in ovary. Down-regulated in brains from Parkinson disease and CC Alzheimer disease patients. {ECO:0000269|PubMed:14722078, CC ECO:0000269|PubMed:9790970}. CC -!- PTM: O-glycosylated. {ECO:0000250}. CC -!- DISEASE: Parkinson disease 5 (PARK5) [MIM:613643]: A complex CC neurodegenerative disorder with manifestations ranging from typical CC Parkinson disease to dementia with Lewy bodies. Clinical features CC include parkinsonian symptoms (resting tremor, rigidity, postural CC instability and bradykinesia), dementia, diffuse Lewy body pathology, CC autonomic dysfunction, hallucinations and paranoia. CC {ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903, CC ECO:0000269|PubMed:9774100}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- DISEASE: Spastic paraplegia 79A, autosomal dominant, with ataxia CC (SPG79A) [MIM:620221]: A form of spastic paraplegia, a CC neurodegenerative disorder characterized by a slow, gradual, CC progressive weakness and spasticity of the lower limbs. Rate of CC progression and the severity of symptoms are quite variable. Initial CC symptoms may include difficulty with balance, weakness and stiffness in CC the legs, muscle spasms, and dragging the toes when walking. In some CC forms of the disorder, bladder symptoms (such as incontinence) may CC appear, or the weakness and stiffness may spread to other parts of the CC body. SPG79A is a slowly progressive form characterized by late-onset CC spastic ataxia, neuropathy, and often optic atrophy. CC {ECO:0000269|PubMed:35986737}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Spastic paraplegia 79B, autosomal recessive (SPG79B) CC [MIM:615491]: A form of spastic paraplegia, a neurodegenerative CC disorder characterized by a slow, gradual, progressive weakness and CC spasticity of the lower limbs. Rate of progression and the severity of CC symptoms are quite variable. Initial symptoms may include difficulty CC with balance, weakness and stiffness in the legs, muscle spasms, and CC dragging the toes when walking. In some forms of the disorder, bladder CC symptoms (such as incontinence) may appear, or the weakness and CC stiffness may spread to other parts of the body. SPG79B is CC characterized by childhood onset blindness, cerebellar ataxia, CC nystagmus, dorsal column dysfunction, and spasticity with upper motor CC neuron dysfunction. {ECO:0000269|PubMed:23359680, CC ECO:0000269|PubMed:28007905}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: Oxidation of Met-1, Met-6, Met-12, Met-124 and Met-179 CC to methionine sulfoxide, and oxidation of Cys-220 to cysteine sulfonic CC acid have been observed in brains from Alzheimer disease (AD) and CC Parkinson disease (PD) patients. In AD, UCHL1 was found to be CC associated with neurofibrillary tangles. In contrast to UCHL3, does not CC hydrolyze a peptide bond at the C-terminal glycine of NEDD8. CC -!- SIMILARITY: Belongs to the peptidase C12 family. {ECO:0000305}. CC -!- CAUTION: PubMed:9774100 reports the association of mutation Ile93Met CC with Parkinson disease. However, according to PubMed:16450370 this CC association is uncertain and UCHL1 is not a susceptibility gene for CC Parkinson disease. {ECO:0000305}. CC -!- CAUTION: The oxidation forms of Met-1, Met-6, Met-12, Met-124, Met-179 CC and Cys-220 are subject of controversy and could be the artifactual CC results of sample handling. {ECO:0000305|PubMed:14722078}. CC -!- CAUTION: The homodimer may have ATP-independent ubiquitin ligase CC activity (PubMed:12408865). However, in another study, UCHL1 was shown CC to lack ubiquitin ligase activity (PubMed:23359680). CC {ECO:0000269|PubMed:23359680, ECO:0000305|PubMed:12408865}. CC -!- SEQUENCE CAUTION: CC Sequence=CAA28443.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Wikipedia; Note=Ubiquitin carboxy-terminal hydrolase CC L1 entry; CC URL="https://en.wikipedia.org/wiki/Ubiquitin_carboxy-terminal_hydrolase_L1"; 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; AC095043; AAY40923.1; -; Genomic_DNA. DR EMBL; CH471069; EAW92983.1; -; Genomic_DNA. DR EMBL; BC000332; AAH00332.1; -; mRNA. DR EMBL; BC005117; AAH05117.1; -; mRNA. DR EMBL; BC006305; AAH06305.1; -; mRNA. DR EMBL; X17377; CAA35249.1; -; Genomic_DNA. DR EMBL; X04741; CAA28443.1; ALT_INIT; mRNA. DR EMBL; AH007277; AAD09172.1; -; Genomic_DNA. DR CCDS; CCDS3462.1; -. [P09936-1] DR PIR; A25856; A25856. DR RefSeq; NP_004172.2; NM_004181.4. [P09936-1] DR PDB; 2ETL; X-ray; 2.40 A; A/B=1-223. DR PDB; 2LEN; NMR; -; A=1-223. DR PDB; 3IFW; X-ray; 2.40 A; A=1-223. DR PDB; 3IRT; X-ray; 2.80 A; A/B=1-223. DR PDB; 3KVF; X-ray; 2.80 A; A=1-223. DR PDB; 3KW5; X-ray; 2.83 A; A=1-223. DR PDB; 4DM9; X-ray; 2.35 A; A/B=1-223. DR PDB; 4JKJ; X-ray; 2.15 A; A/B=1-223. DR PDB; 7ZM0; X-ray; 2.24 A; A/B/C/D/E/F/G/H/I/J=1-223. DR PDB; 8DY8; X-ray; 2.10 A; A/B=1-223. DR PDB; 8EDE; X-ray; 1.80 A; A/B=1-223. DR PDB; 8PW1; X-ray; 2.20 A; A/B/C/D/E/F/G/H/I/J=1-223. DR PDB; 8XI7; X-ray; 1.95 A; A/B=1-223. DR PDB; 9O4M; X-ray; 2.00 A; A/B=1-223. DR PDBsum; 2ETL; -. DR PDBsum; 2LEN; -. DR PDBsum; 3IFW; -. DR PDBsum; 3IRT; -. DR PDBsum; 3KVF; -. DR PDBsum; 3KW5; -. DR PDBsum; 4DM9; -. DR PDBsum; 4JKJ; -. DR PDBsum; 7ZM0; -. DR PDBsum; 8DY8; -. DR PDBsum; 8EDE; -. DR PDBsum; 8PW1; -. DR PDBsum; 8XI7; -. DR PDBsum; 9O4M; -. DR AlphaFoldDB; P09936; -. DR BMRB; P09936; -. DR SASBDB; P09936; -. DR SMR; P09936; -. DR BioGRID; 113192; 258. DR CORUM; P09936; -. DR DIP; DIP-36620N; -. DR FunCoup; P09936; 1475. DR IntAct; P09936; 199. DR MINT; P09936; -. DR STRING; 9606.ENSP00000284440; -. DR BindingDB; P09936; -. DR ChEMBL; CHEMBL6159; -. DR DrugBank; DB12695; Phenethyl Isothiocyanate. DR GuidetoPHARMACOLOGY; 2426; -. DR MEROPS; C12.001; -. DR GlyGen; P09936; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P09936; -. DR MetOSite; P09936; -. DR PhosphoSitePlus; P09936; -. DR SwissPalm; P09936; -. DR BioMuta; UCHL1; -. DR DMDM; 136681; -. DR CPTAC; CPTAC-601; -. DR CPTAC; CPTAC-602; -. DR jPOST; P09936; -. DR MassIVE; P09936; -. DR PaxDb; 9606-ENSP00000284440; -. DR PeptideAtlas; P09936; -. DR ProteomicsDB; 52282; -. DR Pumba; P09936; -. DR Antibodypedia; 1062; 2368 antibodies from 53 providers. DR DNASU; 7345; -. DR Ensembl; ENST00000284440.9; ENSP00000284440.4; ENSG00000154277.14. [P09936-1] DR Ensembl; ENST00000503431.5; ENSP00000422542.1; ENSG00000154277.14. [P09936-1] DR GeneID; 7345; -. DR KEGG; hsa:7345; -. DR MANE-Select; ENST00000284440.9; ENSP00000284440.4; NM_004181.5; NP_004172.2. DR AGR; HGNC:12513; -. DR ClinPGx; PA37160; -. DR CTD; 7345; -. DR DisGeNET; 7345; -. DR GeneCards; UCHL1; -. DR HGNC; HGNC:12513; UCHL1. DR HPA; ENSG00000154277; Group enriched (brain, pituitary gland). DR MalaCards; UCHL1; -. DR MIM; 191342; gene. DR MIM; 613643; phenotype. DR MIM; 615491; phenotype. DR MIM; 620221; phenotype. DR OpenTargets; ENSG00000154277; -. DR Orphanet; 352654; Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000154277; -. DR eggNOG; KOG1415; Eukaryota. DR GeneTree; ENSGT00940000157306; -. DR HOGENOM; CLU_054406_2_0_1; -. DR InParanoid; P09936; -. DR OMA; AQTYSKH; -. DR OrthoDB; 427186at2759; -. DR PAN-GO; P09936; 3 GO annotations based on evolutionary models. DR PhylomeDB; P09936; -. DR BRENDA; 3.4.19.12; 2681. DR PathwayCommons; P09936; -. DR Reactome; R-HSA-5689603; UCH proteinases. DR SABIO-RK; P09936; -. DR SignaLink; P09936; -. DR SIGNOR; P09936; -. DR Agora; ENSG00000154277; -. DR BioGRID-ORCS; 7345; 9 hits in 1196 CRISPR screens. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; UCHL1; human. DR EvolutionaryTrace; P09936; -. DR GeneWiki; Ubiquitin_carboxy-terminal_hydrolase_L1; -. DR GenomeRNAi; 7345; -. DR Pharos; P09936; Tchem. DR PRO; PR:P09936; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; P09936; protein. DR Bgee; ENSG00000154277; Expressed in pons and 169 other cell types or tissues. DR ExpressionAtlas; P09936; baseline and differential. DR GO; GO:1904115; C:axon cytoplasm; IEA:GOC. DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0044306; C:neuron projection terminus; IEA:Ensembl. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0031694; F:alpha-2A adrenergic receptor binding; IPI:BHF-UCL. DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB. DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IDA:UniProtKB. DR GO; GO:0008242; F:omega peptidase activity; IDA:UniProtKB. DR GO; GO:0043022; F:ribosome binding; IEA:Ensembl. DR GO; GO:0030547; F:signaling receptor inhibitor activity; IDA:BHF-UCL. DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0007628; P:adult walking behavior; IEA:Ensembl. DR GO; GO:0007412; P:axon target recognition; IEA:Ensembl. DR GO; GO:0019896; P:axonal transport of mitochondrion; IEA:Ensembl. DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0042755; P:eating behavior; IEA:Ensembl. DR GO; GO:0002176; P:male germ cell proliferation; IEA:Ensembl. DR GO; GO:0055001; P:muscle cell development; IEA:Ensembl. DR GO; GO:0043409; P:negative regulation of MAPK cascade; IDA:BHF-UCL. DR GO; GO:0050905; P:neuromuscular process; IEA:Ensembl. DR GO; GO:0045821; P:positive regulation of glycolytic process; IMP:FlyBase. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; NAS:ParkinsonsUK-UCL. DR GO; GO:0030163; P:protein catabolic process; IBA:GO_Central. DR GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB. DR GO; GO:0016241; P:regulation of macroautophagy; TAS:ParkinsonsUK-UCL. DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl. DR CDD; cd09616; Peptidase_C12_UCH_L1_L3; 1. DR FunFam; 3.40.532.10:FF:000004; Ubiquitin carboxyl-terminal hydrolase; 1. DR Gene3D; 3.40.532.10; Peptidase C12, ubiquitin carboxyl-terminal hydrolase; 1. DR InterPro; IPR038765; Papain-like_cys_pep_sf. DR InterPro; IPR001578; Peptidase_C12_UCH. DR InterPro; IPR036959; Peptidase_C12_UCH_sf. DR InterPro; IPR057254; UCH_AS. DR PANTHER; PTHR10589; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE; 1. DR PANTHER; PTHR10589:SF19; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE ISOZYME L1; 1. DR Pfam; PF01088; Peptidase_C12; 1. DR PRINTS; PR00707; UBCTHYDRLASE. DR SUPFAM; SSF54001; Cysteine proteinases; 1. DR PROSITE; PS00140; UCH_1; 1. DR PROSITE; PS52048; UCH_DOMAIN; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative initiation; Cytoplasm; KW Direct protein sequencing; Disease variant; Endoplasmic reticulum; KW Glycoprotein; Hereditary spastic paraplegia; Hydrolase; Lipoprotein; KW Membrane; Neurodegeneration; Oxidation; Parkinson disease; Parkinsonism; KW Phosphoprotein; Prenylation; Protease; Proteomics identification; KW Reference proteome; Thiol protease; Ubl conjugation pathway. FT CHAIN 1..220 FT /note="Ubiquitin carboxyl-terminal hydrolase isozyme L1" FT /id="PRO_0000211055" FT PROPEP 221..223 FT /note="Removed in mature form" FT /evidence="ECO:0000305" FT /id="PRO_0000414311" FT DOMAIN 2..221 FT /note="UCH catalytic" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393" FT REGION 5..10 FT /note="Interaction with ubiquitin" FT /evidence="ECO:0000269|PubMed:20439756" FT REGION 211..216 FT /note="Interaction with ubiquitin" FT /evidence="ECO:0000269|PubMed:20439756" FT ACT_SITE 90 FT /note="Nucleophile" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393, FT ECO:0000269|PubMed:20439756" FT ACT_SITE 161 FT /note="Proton donor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393, FT ECO:0000269|PubMed:20439756" FT SITE 1 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 6 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 12 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 84 FT /note="Transition state stabilizer" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393, FT ECO:0000269|PubMed:8639624" FT SITE 124 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 176 FT /note="Important for enzyme activity" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393" FT SITE 179 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 220 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000269|PubMed:37316325" FT MOD_RES 125 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q00981" FT LIPID 220 FT /note="S-farnesyl cysteine" FT /evidence="ECO:0000269|PubMed:19261853" FT VAR_SEQ 1..11 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000269|PubMed:37316325" FT /id="VSP_062523" FT VAR_SEQ 1..5 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000269|PubMed:37316325" FT /id="VSP_062524" FT VARIANT 2..223 FT /note="Missing (in SPG79A)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087898" FT VARIANT 7 FT /note="E -> A (in SPG79B; has decreased binding to FT ubiquitin and significantly decreased hydrolase activity FT compared to wild-type; dbSNP:rs397515634)" FT /evidence="ECO:0000269|PubMed:23359680" FT /id="VAR_070875" FT VARIANT 18 FT /note="S -> Y (it confers protection from oxidative stress FT when expressed at physiological levels in neuroblastoma FT cells and primary cortical neurons; loss of dimerization FT ability; impaired ligase activity; dbSNP:rs5030732)" FT /evidence="ECO:0000269|PubMed:10203348, FT ECO:0000269|PubMed:11027850, ECO:0000269|PubMed:12408865, FT ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:15048890, FT ECO:0000269|PubMed:16450370, ECO:0000269|PubMed:18411255, FT ECO:0000269|PubMed:21268678" FT /id="VAR_015677" FT VARIANT 25..223 FT /note="Missing (in SPG79A)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087899" FT VARIANT 52 FT /note="L -> LL (in SPG79A; uncertain significance)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087900" FT VARIANT 93 FT /note="I -> M (in PARK5; impaired enzymatic hydrolase FT activity; has about a 50% reduction in catalytic activity FT compared to wild-type protein; dbSNP:rs121917767)" FT /evidence="ECO:0000269|PubMed:10454131, FT ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903, FT ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:9774100" FT /id="VAR_015678" FT VARIANT 178..223 FT /note="Missing (in SPG79A)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087901" FT VARIANT 178 FT /note="R -> Q (in SPG79B; increased hydrolase activity; FT decreased protein abundance; dbSNP:rs768996179)" FT /evidence="ECO:0000269|PubMed:28007905" FT /id="VAR_078119" FT VARIANT 211..223 FT /note="Missing (in SPG79A)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087902" FT VARIANT 216 FT /note="A -> D (in SPG79B; decreased protein abundance; FT dbSNP:rs1057519600)" FT /evidence="ECO:0000269|PubMed:28007905" FT /id="VAR_078120" FT MUTAGEN 73 FT /note="Q->R: No effect on enzymatic parameters." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 90 FT /note="C->S: Abolishes enzymatic activity." FT /evidence="ECO:0000269|PubMed:12705903, FT ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680, FT ECO:0000269|PubMed:25615526, ECO:0000269|PubMed:8639624" FT MUTAGEN 97 FT /note="H->Q,N: 2-fold increase in affinity for ubiquitin FT ethyl ester, slight reduction in enzymatic activity." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 161 FT /note="H->D: 10000-fold decrease in enzymatic activity; no FT change in affinity for ubiquitin ethyl ester." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 161 FT /note="H->K,Q,N,Y: Abolishes enzymatic activity." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 176 FT /note="D->N: 6-fold decrease in affinity for ubiquitin FT ethyl ester; 97.5% decrease in enzymatic activity." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 204 FT /note="F->A: Almost complete loss of activity." FT /evidence="ECO:0000269|PubMed:20439756" FT HELIX 10..19 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 22..25 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 27..31 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 36..41 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 46..54 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 57..70 FT /evidence="ECO:0007829|PDB:8EDE" FT TURN 71..74 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 86..88 FT /evidence="ECO:0007829|PDB:2LEN" FT HELIX 90..100 FT /evidence="ECO:0007829|PDB:8EDE" FT TURN 101..105 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 113..120 FT /evidence="ECO:0007829|PDB:8EDE" FT TURN 121..123 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 126..135 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 137..147 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 160..168 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 171..175 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 179..181 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 183..187 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 190..192 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 193..207 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 211..213 FT /evidence="ECO:0007829|PDB:2LEN" FT STRAND 215..220 FT /evidence="ECO:0007829|PDB:8EDE" FT MOD_RES P09936-2:1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000269|PubMed:37316325" FT MOD_RES P09936-3:1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000269|PubMed:37316325" SQ SEQUENCE 223 AA; 24824 MW; C9E972AC4DA5DA8A CRC64; MQLKPMEINP EMLNKVLSRL GVAGQWRFVD VLGLEEESLG SVPAPACALL LLFPLTAQHE NFRKKQIEEL KGQEVSPKVY FMKQTIGNSC GTIGLIHAVA NNQDKLGFED GSVLKQFLSE TEKMSPEDRA KCFEKNEAIQ AAHDAVAQEG QCRVDDKVNF HFILFNNVDG HLYELDGRMP FPVNHGASSE DTLLKDAAKV CREFTEREQG EVRFSAVALC KAA //