ID PCSK9_HUMAN Reviewed; 692 AA. AC Q8NBP7; A8T640; C0JYY9; Q5PSM5; Q5SZQ2; DT 07-NOV-2003, integrated into UniProtKB/Swiss-Prot. DT 11-JAN-2011, sequence version 3. DT 27-MAR-2024, entry version 209. DE RecName: Full=Proprotein convertase subtilisin/kexin type 9; DE EC=3.4.21.-; DE AltName: Full=Neural apoptosis-regulated convertase 1; DE Short=NARC-1; DE AltName: Full=Proprotein convertase 9; DE Short=PC9; DE AltName: Full=Subtilisin/kexin-like protease PC9; DE Flags: Precursor; GN Name=PCSK9; Synonyms=NARC1; ORFNames=PSEC0052; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS ILE-474 AND GLU-670. RA Chiang L.W.; RT "Nucleic acid molecules derived from rat brain and programmed cell death RT models."; RL Patent number WO0131007, 03-MAY-2001. RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS ILE-474 AND GLU-670. RX PubMed=17971861; DOI=10.1371/journal.pone.0001098; RA Ding K., McDonough S.J., Kullo I.J.; RT "Evidence for positive selection in the C-terminal domain of the RT cholesterol metabolism gene PCSK9 based on phylogenetic analysis in 14 RT primate species."; RL PLoS ONE 2:E1098-E1098(2007). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT RP ILE-474. RC TISSUE=Cerebellum, and Teratocarcinoma; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LEU-23 INS; LEU-46; VAL-53; RP SER-425; THR-443; ILE-474; ARG-553; PRO-619 AND GLU-670. RG SeattleSNPs variation discovery resource; RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LEU-23 INS; ILE-474 AND RP GLU-670. RG NHLBI resequencing and genotyping service (RS&G); RL Submitted (DEC-2008) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANTS ILE-474 AND RP GLU-670. 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 PROTEIN SEQUENCE OF N-TERMINUS, CHARACTERIZATION, AND MUTAGENESIS OF RP CYS-67; HIS-226 AND ASN-533. RX PubMed=12552133; DOI=10.1073/pnas.0335507100; RA Seidah N.G., Benjannet S., Wickham L., Marcinkiewicz J., Jasmin S.B., RA Stifani S., Basak A., Prat A., Chretien M.; RT "The secretory proprotein convertase neural apoptosis-regulated convertase RT 1 (NARC-1): liver regeneration and neuronal differentiation."; RL Proc. Natl. Acad. Sci. U.S.A. 100:928-933(2003). RN [9] RP AUTOCATALYTIC CLEAVAGE AT GLN-152. RX PubMed=14622975; DOI=10.1016/j.abb.2003.09.011; RA Naureckiene S., Ma L., Sreekumar K., Purandare U., Lo C.F., Huang Y., RA Chiang L.W., Grenier J.M., Ozenberger B.A., Jacobsen J.S., Kennedy J.D., RA DiStefano P.S., Wood A., Bingham B.; RT "Functional characterization of Narc 1, a novel proteinase related to RT proteinase K."; RL Arch. Biochem. Biophys. 420:55-67(2003). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-688, 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 [11] RP GLYCOSYLATION AT ASN-533, SULFATION AT TYR-38, AND PROTEOLYTIC CLEAVAGE AT RP ARG-218 BY FURIN AND PCSK5. RX PubMed=16912035; DOI=10.1074/jbc.m606495200; RA Benjannet S., Rhainds D., Hamelin J., Nassoury N., Seidah N.G.; RT "The proprotein convertase (PC) PCSK9 is inactivated by furin and/or RT PC5/6A: functional consequences of natural mutations and post-translational RT modifications."; RL J. Biol. Chem. 281:30561-30572(2006). RN [12] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH LDLR. RX PubMed=17461796; DOI=10.1111/j.1600-0854.2007.00562.x; RA Nassoury N., Blasiole D.A., Tebon Oler A., Benjannet S., Hamelin J., RA Poupon V., McPherson P.S., Attie A.D., Prat A., Seidah N.G.; RT "The cellular trafficking of the secretory proprotein convertase PCSK9 and RT its dependence on the LDLR."; RL Traffic 8:718-732(2007). RN [13] RP FUNCTION, AND SUBUNIT. RX PubMed=18197702; DOI=10.1021/bi7016359; RA Fan D., Yancey P.G., Qiu S., Ding L., Weeber E.J., Linton M.F., Fazio S.; RT "Self-association of human PCSK9 correlates with its LDLR-degrading RT activity."; RL Biochemistry 47:1631-1639(2008). RN [14] RP FUNCTION, AND INTERACTION WITH BACE1. RX PubMed=18660751; DOI=10.1038/embor.2008.132; RA Jonas M.C., Costantini C., Puglielli L.; RT "PCSK9 is required for the disposal of non-acetylated intermediates of the RT nascent membrane protein BACE1."; RL EMBO Rep. 9:916-922(2008). RN [15] RP PHOSPHORYLATION AT SER-47 AND SER-688, AND IDENTIFICATION BY MASS RP SPECTROMETRY. RX PubMed=18498363; DOI=10.1111/j.1742-4658.2008.06495.x; RA Dewpura T., Raymond A., Hamelin J., Seidah N.G., Mbikay M., Chretien M., RA Mayne J.; RT "PCSK9 is phosphorylated by a Golgi casein kinase-like kinase ex vivo and RT circulates as a phosphoprotein in humans."; RL FEBS J. 275:3480-3493(2008). RN [16] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH VLDLR AND LRP8/APOER2. RX PubMed=18039658; DOI=10.1074/jbc.m708098200; RA Poirier S., Mayer G., Benjannet S., Bergeron E., Marcinkiewicz J., RA Nassoury N., Mayer H., Nimpf J., Prat A., Seidah N.G.; RT "The proprotein convertase PCSK9 induces the degradation of low density RT lipoprotein receptor (LDLR) and its closest family members VLDLR and RT ApoER2."; RL J. Biol. Chem. 283:2363-2372(2008). RN [17] RP FUNCTION, INTERACTION WITH ANXA2, VARIANT FHCL3 TYR-374, CHARACTERIZATION RP OF VARIANT FHCL3 TYR-374, VARIANT GLU-554, AND CHARACTERIZATION OF VARIANT RP GLU-554. RX PubMed=18799458; DOI=10.1074/jbc.m805971200; RA Mayer G., Poirier S., Seidah N.G.; RT "Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous RT low density lipoprotein receptor levels."; RL J. Biol. Chem. 283:31791-31801(2008). RN [18] 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 [19] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-688, 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 [20] RP FUNCTION. RX PubMed=22074827; DOI=10.1016/j.bbrc.2011.10.110; RA Chen Y., Wang H., Yu L., Yu X., Qian Y.W., Cao G., Wang J.; RT "Role of ubiquitination in PCSK9-mediated low-density lipoprotein receptor RT degradation."; RL Biochem. Biophys. Res. Commun. 415:515-518(2011). RN [21] RP INTERACTION WITH LDLR. RX PubMed=21149300; DOI=10.1074/jbc.m110.199042; RA Yamamoto T., Lu C., Ryan R.O.; RT "A two-step binding model of PCSK9 interaction with the low density RT lipoprotein receptor."; RL J. Biol. Chem. 286:5464-5470(2011). RN [22] RP DOMAIN C-TERMINAL. RX PubMed=22027821; DOI=10.1074/jbc.m111.273474; RA Du F., Hui Y., Zhang M., Linton M.F., Fazio S., Fan D.; RT "Novel domain interaction regulates secretion of proprotein convertase RT subtilisin/kexin type 9 (PCSK9) protein."; RL J. Biol. Chem. 286:43054-43061(2011). RN [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-688, AND IDENTIFICATION BY RP 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 [24] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH APOB. RX PubMed=22580899; DOI=10.1161/atvbaha.112.250043; RA Sun H., Samarghandi A., Zhang N., Yao Z., Xiong M., Teng B.B.; RT "Proprotein convertase subtilisin/kexin type 9 interacts with RT apolipoprotein B and prevents its intracellular degradation, irrespective RT of the low-density lipoprotein receptor."; RL Arterioscler. Thromb. Vasc. Biol. 32:1585-1595(2012). RN [25] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-688, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [26] RP PHOSPHORYLATION AT SER-47 AND SER-688. RX PubMed=26091039; DOI=10.1016/j.cell.2015.05.028; RA Tagliabracci V.S., Wiley S.E., Guo X., Kinch L.N., Durrant E., Wen J., RA Xiao J., Cui J., Nguyen K.B., Engel J.L., Coon J.J., Grishin N., RA Pinna L.A., Pagliarini D.J., Dixon J.E.; RT "A single kinase generates the majority of the secreted phosphoproteome."; RL Cell 161:1619-1632(2015). RN [27] RP REVIEW. RX PubMed=18280815; DOI=10.1016/j.bbalip.2008.01.003; RA Lopez D.; RT "PCSK9: an enigmatic protease."; RL Biochim. Biophys. Acta 1781:184-191(2008). RN [28] RP REVIEW. RX PubMed=18649882; DOI=10.1016/j.atherosclerosis.2008.06.010; RA Lambert G., Charlton F., Rye K.A., Piper D.E.; RT "Molecular basis of PCSK9 function."; RL Atherosclerosis 203:1-7(2009). RN [29] RP REVIEW. RX PubMed=19930098; DOI=10.1111/j.1365-2796.2009.02167.x; RA Mousavi S.A., Berge K.E., Leren T.P.; RT "The unique role of proprotein convertase subtilisin/kexin 9 in cholesterol RT homeostasis."; RL J. Intern. Med. 266:507-519(2009). RN [30] RP REVIEW. RX PubMed=19020338; DOI=10.1194/jlr.r800091-jlr200; RA Horton J.D., Cohen J.C., Hobbs H.H.; RT "PCSK9: a convertase that coordinates LDL catabolism."; RL J. Lipid Res. 50:S172-S177(2009). RN [31] RP REVIEW. RX PubMed=21943799; DOI=10.1016/j.numecd.2011.06.002; RA Tibolla G., Norata G.D., Artali R., Meneghetti F., Catapano A.L.; RT "Proprotein convertase subtilisin/kexin type 9 (PCSK9): from structure- RT function relation to therapeutic inhibition."; RL Nutr. Metab. Cardiovasc. Dis. 21:835-843(2011). RN [32] RP REVIEW ON VARIANTS. RX PubMed=19191301; DOI=10.1002/humu.20882; RA Abifadel M., Rabes J.P., Devillers M., Munnich A., Erlich D., Junien C., RA Varret M., Boileau C.; RT "Mutations and polymorphisms in the proprotein convertase subtilisin kexin RT 9 (PCSK9) gene in cholesterol metabolism and disease."; RL Hum. Mutat. 30:520-529(2009). RN [33] RP POLYMORPHISM, AND VARIANT SER-174. RX PubMed=22417841; DOI=10.1016/j.atherosclerosis.2012.02.018; RA Slimani A., Jelassi A., Jguirim I., Najah M., Rebhi L., Omezzine A., RA Maatouk F., Hamda K.B., Kacem M., Rabes J.P., Abifadel M., Boileau C., RA Rouis M., Slimane M.N., Varret M.; RT "Effect of mutations in LDLR and PCSK9 genes on phenotypic variability in RT Tunisian familial hypercholesterolemia patients."; RL Atherosclerosis 222:158-166(2012). RN [34] RP FUNCTION, AND INTERACTION WITH SCNN1A; SCNN1B AND SCNN1G. RX PubMed=22493497; DOI=10.1074/jbc.m112.363382; RA Sharotri V., Collier D.M., Olson D.R., Zhou R., Snyder P.M.; RT "Regulation of epithelial sodium channel trafficking by proprotein RT convertase subtilisin/kexin type 9 (PCSK9)."; RL J. Biol. Chem. 287:19266-19274(2012). RN [35] RP FUNCTION, INTERACTION WITH ANXA2, VARIANT GLN-482, CHARACTERIZATION OF RP VARIANT GLN-482, VARIANTS FHCL3 SER-218 AND TYR-374, CHARACTERIZATION OF RP VARIANTS FHCL3 SER-218 AND TYR-374, SULFATION, PHOSPHORYLATION, RP GLYCOSYLATION, AND SUBUNIT. RX PubMed=24808179; DOI=10.1074/jbc.m113.541094; RA Ly K., Saavedra Y.G., Canuel M., Routhier S., Desjardins R., Hamelin J., RA Mayne J., Lazure C., Seidah N.G., Day R.; RT "Annexin A2 reduces PCSK9 protein levels via a translational mechanism and RT interacts with the M1 and M2 domains of PCSK9."; RL J. Biol. Chem. 289:17732-17746(2014). RN [36] RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 31-692. RX PubMed=17502100; DOI=10.1016/j.str.2007.04.004; RA Piper D.E., Jackson S., Liu Q., Romanow W.G., Shetterly S., Thibault S.T., RA Shan B., Walker N.P.; RT "The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol."; RL Structure 15:545-552(2007). RN [37] RP VARIANTS FHCL3 ARG-127 AND LEU-216, AND VARIANTS LEU-46; VAL-53 AND RP GLU-670. RX PubMed=12730697; DOI=10.1038/ng1161; RA Abifadel M., Varret M., Rabes J.-P., Allard D., Ouguerram K., Devillers M., RA Cruaud C., Benjannet S., Wickham L., Erlich D., Derre A., Villeger L., RA Farnier M., Beucler I., Bruckert E., Chambaz J., Chanu B., Lecerf J.-M., RA Luc G., Moulin P., Weissenbach J., Prat A., Krempf M., Junien C., RA Seidah N.G., Boileau C.; RT "Mutations in PCSK9 cause autosomal dominant hypercholesterolemia."; RL Nat. Genet. 34:154-156(2003). RN [38] RP VARIANTS LEU-46; VAL-53; LYS-57; TRP-237; PHE-253; ASN-391; GLN-417; RP SER-425; THR-443; TRP-469; ILE-474; GLY-482; LEU-515; ARG-553; GLU-554; RP PRO-619 AND GLU-670. RX PubMed=16465619; DOI=10.1086/500615; RA Kotowski I.K., Pertsemlidis A., Luke A., Cooper R.S., Vega G.L., RA Cohen J.C., Hobbs H.H.; RT "A spectrum of PCSK9 alleles contributes to plasma levels of low-density RT lipoprotein cholesterol."; RL Am. J. Hum. Genet. 78:410-422(2006). RN [39] RP POLYMORPHISM, VARIANT LEU-23 INS, AND IMPACT ON FAMILIAL RP HYPERCHOLESTEROLEMIA. RX PubMed=19319977; DOI=10.1002/humu.21002; RA Abifadel M., Rabes J.-P., Jambart S., Halaby G., Gannage-Yared M.-H., RA Sarkis A., Beaino G., Varret M., Salem N., Corbani S., Aydenian H., RA Junien C., Munnich A., Boileau C.; RT "The molecular basis of familial hypercholesterolemia in Lebanon: spectrum RT of LDLR mutations and role of PCSK9 as a modifier gene."; RL Hum. Mutat. 30:E682-E691(2009). RN [40] RP POLYMORPHISM, VARIANT FHCL3 SER-394, AND VARIANTS LEU-23 INS; LEU-46; RP VAL-53; ILE-474 AND GLU-670. RX PubMed=22095935; DOI=10.1002/humu.21660; RA Huijgen R., Sjouke B., Vis K., de Randamie J.S., Defesche J.C., RA Kastelein J.J., Hovingh G.K., Fouchier S.W.; RT "Genetic variation in APOB, PCSK9, and ANGPTL3 in carriers of pathogenic RT autosomal dominant hypercholesterolemic mutations with unexpected low LDL- RT Cl Levels."; RL Hum. Mutat. 33:448-455(2012). CC -!- FUNCTION: Crucial player in the regulation of plasma cholesterol CC homeostasis. Binds to low-density lipid receptor family members: low CC density lipoprotein receptor (LDLR), very low density lipoprotein CC receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and CC apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation CC in intracellular acidic compartments (PubMed:18039658). Acts via a non- CC proteolytic mechanism to enhance the degradation of the hepatic LDLR CC through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the CC recycling of LDLR from endosomes to the cell surface or direct it to CC lysosomes for degradation. Can induce ubiquitination of LDLR leading to CC its subsequent degradation (PubMed:18799458, PubMed:17461796, CC PubMed:18197702, PubMed:22074827). Inhibits intracellular degradation CC of APOB via the autophagosome/lysosome pathway in a LDLR-independent CC manner. Involved in the disposal of non-acetylated intermediates of CC BACE1 in the early secretory pathway (PubMed:18660751). Inhibits CC epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing CC ENaC surface expression primarily by increasing its proteasomal CC degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 CC levels and related anti-apoptotic signaling pathways. CC {ECO:0000269|PubMed:17461796, ECO:0000269|PubMed:18039658, CC ECO:0000269|PubMed:18197702, ECO:0000269|PubMed:18660751, CC ECO:0000269|PubMed:18799458, ECO:0000269|PubMed:22074827, CC ECO:0000269|PubMed:22493497, ECO:0000269|PubMed:22580899}. CC -!- COFACTOR: CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000305}; CC -!- ACTIVITY REGULATION: Its proteolytic activity is autoinhibited by the CC non-covalent binding of the propeptide to the catalytic domain. CC Inhibited by EGTA. CC -!- SUBUNIT: Monomer. Can self-associate to form dimers and higher CC multimers which may have increased LDLR degrading activity. The CC precursor protein but not the mature protein may form multimers. CC Interacts with APOB, VLDLR, LRP8/APOER2 and BACE1. The full-length CC immature form (pro-PCSK9) interacts with SCNN1A, SCNN1B and SCNN1G. The CC pro-PCSK9 form (via C-terminal domain) interacts with LDLR. Interacts CC (via the C-terminal domain) with ANXA2 (via repeat Annexin 1); the CC interaction inhibits the degradation of LDLR (PubMed:18799458). CC {ECO:0000269|PubMed:17461796, ECO:0000269|PubMed:18039658, CC ECO:0000269|PubMed:18197702, ECO:0000269|PubMed:18660751, CC ECO:0000269|PubMed:18799458, ECO:0000269|PubMed:21149300, CC ECO:0000269|PubMed:22493497, ECO:0000269|PubMed:22580899, CC ECO:0000269|PubMed:24808179}. CC -!- INTERACTION: CC Q8NBP7; P07355: ANXA2; NbExp=7; IntAct=EBI-7539251, EBI-352622; CC Q8NBP7; P01130: LDLR; NbExp=10; IntAct=EBI-7539251, EBI-988319; CC Q8NBP7; P08253: MMP2; NbExp=4; IntAct=EBI-7539251, EBI-1033518; CC Q8NBP7-1; P01130: LDLR; NbExp=4; IntAct=EBI-15656131, EBI-988319; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Secreted. Endosome. Lysosome. Cell CC surface. Endoplasmic reticulum. Golgi apparatus. Note=Autocatalytic CC cleavage is required to transport it from the endoplasmic reticulum to CC the Golgi apparatus and for the secretion of the mature protein. CC Localizes to the endoplasmic reticulum in the absence of LDLR and CC colocalizes to the cell surface and to the endosomes/lysosomes in the CC presence of LDLR. The sorting to the cell surface and endosomes is CC required in order to fully promote LDLR degradation. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q8NBP7-1; Sequence=Displayed; CC Name=2; CC IsoId=Q8NBP7-2; Sequence=VSP_008844, VSP_008845, VSP_008846; CC -!- TISSUE SPECIFICITY: Expressed in neuro-epithelioma, colon carcinoma, CC hepatic and pancreatic cell lines, and in Schwann cells. CC -!- DOMAIN: The C-terminal domain (CRD) is essential for the LDLR-binding CC and degrading activities. {ECO:0000269|PubMed:22027821}. CC -!- DOMAIN: The catalytic domain is responsible for mediating its self- CC association. {ECO:0000269|PubMed:22027821}. CC -!- PTM: Cleavage by furin and PCSK5 generates a truncated inactive protein CC that is unable to induce LDLR degradation. CC {ECO:0000269|PubMed:16912035}. CC -!- PTM: Undergoes autocatalytic cleavage in the endoplasmic reticulum to CC release the propeptide from the N-terminus and the cleavage of the CC propeptide is strictly required for its maturation and activation. The CC cleaved propeptide however remains associated with the catalytic domain CC through non-covalent interactions, preventing potential substrates from CC accessing its active site. As a result, it is secreted from cells as a CC propeptide-containing, enzymatically inactive protein. CC {ECO:0000269|PubMed:14622975}. CC -!- PTM: Phosphorylation protects the propeptide against proteolysis. CC {ECO:0000269|PubMed:18498363}. CC -!- POLYMORPHISM: Variant Leu-23 ins polymorphism in PCSK9 might have a CC modifier effect on LDLR mutation and familial hypercholesterolemia. CC -!- POLYMORPHISM: Genetic variations in PCSK9 define the low density CC lipoprotein cholesterol level quantitative trait locus 1 (LDLCQ1) CC [MIM:603776]. {ECO:0000269|PubMed:19319977, CC ECO:0000269|PubMed:22095935, ECO:0000269|PubMed:22417841}. CC -!- DISEASE: Hypercholesterolemia, familial, 3 (FHCL3) [MIM:603776]: A form CC of hypercholesterolemia, a disorder of lipoprotein metabolism CC characterized by elevated serum low-density lipoprotein (LDL) CC cholesterol levels, which result in excess deposition of cholesterol in CC tissues and leads to xanthelasma, xanthomas, accelerated CC atherosclerosis and increased risk of premature coronary heart disease. CC FHCL3 inheritance is autosomal dominant. {ECO:0000269|PubMed:12730697, CC ECO:0000269|PubMed:18799458, ECO:0000269|PubMed:22095935, CC ECO:0000269|PubMed:24808179}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the peptidase S8 family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAC11572.1; Type=Frameshift; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=SeattleSNPs; CC URL="http://pga.gs.washington.edu/data/pcsk9/"; 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; AX127530; CAC38896.1; -; mRNA. DR EMBL; EF692496; ABV59216.1; -; mRNA. DR EMBL; AK075365; BAC11572.1; ALT_FRAME; mRNA. DR EMBL; AK124635; BAC85910.1; -; mRNA. DR EMBL; AY829011; AAV67948.1; -; Genomic_DNA. DR EMBL; FJ525880; ACN81318.1; -; Genomic_DNA. DR EMBL; AC091609; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL589790; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471059; EAX06660.1; -; Genomic_DNA. DR CCDS; CCDS603.1; -. [Q8NBP7-1] DR RefSeq; NP_777596.2; NM_174936.3. [Q8NBP7-1] DR PDB; 2P4E; X-ray; 1.98 A; A/P=1-692. DR PDB; 2PMW; X-ray; 2.30 A; A=31-152, B=153-692. DR PDB; 2QTW; X-ray; 1.90 A; A=29-152, B=153-692. DR PDB; 2W2M; X-ray; 2.40 A; A=153-451, P=53-152. DR PDB; 2W2N; X-ray; 2.30 A; A=153-451, P=53-152. DR PDB; 2W2O; X-ray; 2.62 A; A=153-451, P=53-152. DR PDB; 2W2P; X-ray; 2.62 A; A=153-451, P=53-152. DR PDB; 2W2Q; X-ray; 2.33 A; A=153-451, P=53-152. DR PDB; 2XTJ; X-ray; 2.70 A; A=153-451, P=53-152. DR PDB; 3BPS; X-ray; 2.41 A; A=153-692, P=53-152. DR PDB; 3GCW; X-ray; 2.70 A; A=153-692, P=53-152. DR PDB; 3GCX; X-ray; 2.70 A; A=153-692, P=53-152. DR PDB; 3H42; X-ray; 2.30 A; A=31-152, B=153-692. DR PDB; 3M0C; X-ray; 7.01 A; A=29-152, B=153-692. DR PDB; 3P5B; X-ray; 3.30 A; A=153-692, P=61-152. DR PDB; 3P5C; X-ray; 4.20 A; A=153-692, P=61-152. DR PDB; 3SQO; X-ray; 2.70 A; A=153-692, P=31-152. DR PDB; 4K8R; X-ray; 3.22 A; A=61-152, B=153-692. DR PDB; 4NE9; X-ray; 2.60 A; A/B=153-692, C/P=1-152. DR PDB; 4NMX; X-ray; 1.85 A; A=31-152, B=153-452. DR PDB; 4OV6; X-ray; 2.69 A; A/D=60-152, B/E=153-446. DR PDB; 5OCA; X-ray; 2.30 A; A=31-152, B=153-692. DR PDB; 5VL7; X-ray; 3.50 A; A=31-152, B=153-692. DR PDB; 5VLA; X-ray; 2.40 A; A=1-452. DR PDB; 5VLH; X-ray; 2.86 A; A=1-452. DR PDB; 5VLK; X-ray; 2.20 A; A=1-452. DR PDB; 5VLL; X-ray; 2.37 A; A=1-452. DR PDB; 5VLP; X-ray; 2.90 A; A=1-692. DR PDB; 6E4Y; X-ray; 2.24 A; P=32-53. DR PDB; 6E4Z; X-ray; 2.20 A; P=32-53. DR PDB; 6MV5; X-ray; 2.10 A; P=32-53. DR PDB; 6OLZ; EM; 3.90 A; A=9-34. DR PDB; 6OM0; EM; 3.10 A; y=9-34. DR PDB; 6OM7; EM; 3.70 A; y=9-34. DR PDB; 6U26; X-ray; 1.53 A; A/B=31-692. DR PDB; 6U2F; X-ray; 2.94 A; A=1-692. DR PDB; 6U2N; X-ray; 2.15 A; A/B=31-692. DR PDB; 6U2P; X-ray; 2.04 A; A/B=31-692. DR PDB; 6U36; X-ray; 2.70 A; A/B=31-692. DR PDB; 6U38; X-ray; 2.73 A; A/B=31-692. DR PDB; 6U3I; X-ray; 2.90 A; A=1-692. DR PDB; 6U3X; X-ray; 2.64 A; A/B=31-692. DR PDB; 7ANQ; X-ray; 2.20 A; A=452-682. DR PDBsum; 2P4E; -. DR PDBsum; 2PMW; -. DR PDBsum; 2QTW; -. DR PDBsum; 2W2M; -. DR PDBsum; 2W2N; -. DR PDBsum; 2W2O; -. DR PDBsum; 2W2P; -. DR PDBsum; 2W2Q; -. DR PDBsum; 2XTJ; -. DR PDBsum; 3BPS; -. DR PDBsum; 3GCW; -. DR PDBsum; 3GCX; -. DR PDBsum; 3H42; -. DR PDBsum; 3M0C; -. DR PDBsum; 3P5B; -. DR PDBsum; 3P5C; -. DR PDBsum; 3SQO; -. DR PDBsum; 4K8R; -. DR PDBsum; 4NE9; -. DR PDBsum; 4NMX; -. DR PDBsum; 4OV6; -. DR PDBsum; 5OCA; -. DR PDBsum; 5VL7; -. DR PDBsum; 5VLA; -. DR PDBsum; 5VLH; -. DR PDBsum; 5VLK; -. DR PDBsum; 5VLL; -. DR PDBsum; 5VLP; -. DR PDBsum; 6E4Y; -. DR PDBsum; 6E4Z; -. DR PDBsum; 6MV5; -. DR PDBsum; 6OLZ; -. DR PDBsum; 6OM0; -. DR PDBsum; 6OM7; -. DR PDBsum; 6U26; -. DR PDBsum; 6U2F; -. DR PDBsum; 6U2N; -. DR PDBsum; 6U2P; -. DR PDBsum; 6U36; -. DR PDBsum; 6U38; -. DR PDBsum; 6U3I; -. DR PDBsum; 6U3X; -. DR PDBsum; 7ANQ; -. DR AlphaFoldDB; Q8NBP7; -. DR SMR; Q8NBP7; -. DR BioGRID; 129116; 138. DR ComplexPortal; CPX-128; LDLR-PCSK9 complex. DR ComplexPortal; CPX-130; ANXA2-PCSK9 complex. DR DIP; DIP-29694N; -. DR IntAct; Q8NBP7; 5. DR MINT; Q8NBP7; -. DR STRING; 9606.ENSP00000303208; -. DR BindingDB; Q8NBP7; -. DR ChEMBL; CHEMBL2929; -. DR DrugBank; DB09302; Alirocumab. DR DrugBank; DB09303; Evolocumab. DR DrugBank; DB14901; Inclisiran. DR DrugCentral; Q8NBP7; -. DR GuidetoPHARMACOLOGY; 2388; -. DR MEROPS; S08.039; -. DR GlyCosmos; Q8NBP7; 1 site, No reported glycans. DR GlyGen; Q8NBP7; 1 site. DR iPTMnet; Q8NBP7; -. DR PhosphoSitePlus; Q8NBP7; -. DR BioMuta; PCSK9; -. DR DMDM; 317373487; -. DR EPD; Q8NBP7; -. DR jPOST; Q8NBP7; -. DR MassIVE; Q8NBP7; -. DR MaxQB; Q8NBP7; -. DR PaxDb; 9606-ENSP00000303208; -. DR PeptideAtlas; Q8NBP7; -. DR ProteomicsDB; 72807; -. [Q8NBP7-1] DR ProteomicsDB; 72808; -. [Q8NBP7-2] DR Pumba; Q8NBP7; -. DR ABCD; Q8NBP7; 109 sequenced antibodies. DR Antibodypedia; 33231; 1166 antibodies from 44 providers. DR DNASU; 255738; -. DR Ensembl; ENST00000302118.5; ENSP00000303208.5; ENSG00000169174.12. [Q8NBP7-1] DR GeneID; 255738; -. DR KEGG; hsa:255738; -. DR MANE-Select; ENST00000302118.5; ENSP00000303208.5; NM_174936.4; NP_777596.2. DR UCSC; uc001cyf.3; human. [Q8NBP7-1] DR AGR; HGNC:20001; -. DR CTD; 255738; -. DR DisGeNET; 255738; -. DR GeneCards; PCSK9; -. DR GeneReviews; PCSK9; -. DR HGNC; HGNC:20001; PCSK9. DR HPA; ENSG00000169174; Tissue enriched (liver). DR MalaCards; PCSK9; -. DR MIM; 603776; phenotype. DR MIM; 607786; gene. DR neXtProt; NX_Q8NBP7; -. DR OpenTargets; ENSG00000169174; -. DR Orphanet; 391665; Homozygous familial hypercholesterolemia. DR Orphanet; 426; NON RARE IN EUROPE: Familial hypobetalipoproteinemia. DR Orphanet; 406; NON RARE IN EUROPE: Heterozygous familial hypercholesterolemia. DR PharmGKB; PA38617; -. DR VEuPathDB; HostDB:ENSG00000169174; -. DR eggNOG; KOG1153; Eukaryota. DR GeneTree; ENSGT00490000043472; -. DR HOGENOM; CLU_011263_11_0_1; -. DR InParanoid; Q8NBP7; -. DR OMA; GEEMMGC; -. DR OrthoDB; 380531at2759; -. DR PhylomeDB; Q8NBP7; -. DR TreeFam; TF106271; -. DR BRENDA; 3.4.21.61; 2681. DR PathwayCommons; Q8NBP7; -. DR Reactome; R-HSA-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs). DR Reactome; R-HSA-8866427; VLDLR internalisation and degradation. DR Reactome; R-HSA-8957275; Post-translational protein phosphorylation. DR Reactome; R-HSA-8964038; LDL clearance. DR SignaLink; Q8NBP7; -. DR SIGNOR; Q8NBP7; -. DR BioGRID-ORCS; 255738; 37 hits in 1160 CRISPR screens. DR EvolutionaryTrace; Q8NBP7; -. DR GeneWiki; PCSK9; -. DR GenomeRNAi; 255738; -. DR Pharos; Q8NBP7; Tclin. DR PRO; PR:Q8NBP7; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q8NBP7; Protein. DR Bgee; ENSG00000169174; Expressed in right lobe of liver and 114 other cell types or tissues. DR ExpressionAtlas; Q8NBP7; baseline and differential. DR GO; GO:0009986; C:cell surface; IDA:UniProtKB. DR GO; GO:0030134; C:COPII-coated ER to Golgi transport vesicle; IEA:Ensembl. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005769; C:early endosome; IDA:UniProtKB. DR GO; GO:0036020; C:endolysosome membrane; TAS:Reactome. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; IDA:HGNC-UCL. DR GO; GO:0031232; C:extrinsic component of external side of plasma membrane; IC:BHF-UCL. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0005770; C:late endosome; IDA:UniProtKB. DR GO; GO:0005765; C:lysosomal membrane; TAS:Reactome. DR GO; GO:0005764; C:lysosome; IDA:UniProtKB. DR GO; GO:1990667; C:PCSK9-AnxA2 complex; IDA:BHF-UCL. DR GO; GO:1990666; C:PCSK9-LDLR complex; IDA:BHF-UCL. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:BHF-UCL. DR GO; GO:0005886; C:plasma membrane; IDA:BHF-UCL. DR GO; GO:0034185; F:apolipoprotein binding; ISS:UniProtKB. DR GO; GO:0034190; F:apolipoprotein receptor binding; IDA:BHF-UCL. DR GO; GO:0030169; F:low-density lipoprotein particle binding; ISS:UniProtKB. DR GO; GO:0050750; F:low-density lipoprotein particle receptor binding; IDA:HGNC-UCL. DR GO; GO:0043621; F:protein self-association; IDA:UniProtKB. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0004252; F:serine-type endopeptidase activity; IDA:HGNC-UCL. DR GO; GO:0030547; F:signaling receptor inhibitor activity; IDA:BHF-UCL. DR GO; GO:0019871; F:sodium channel inhibitor activity; IDA:UniProtKB. DR GO; GO:0034189; F:very-low-density lipoprotein particle binding; ISS:UniProtKB. DR GO; GO:0070326; F:very-low-density lipoprotein particle receptor binding; IDA:BHF-UCL. DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW. DR GO; GO:0032869; P:cellular response to insulin stimulus; ISS:HGNC-UCL. DR GO; GO:0009267; P:cellular response to starvation; ISS:HGNC-UCL. DR GO; GO:0042632; P:cholesterol homeostasis; IMP:HGNC-UCL. DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW. DR GO; GO:0001822; P:kidney development; ISS:HGNC-UCL. DR GO; GO:0042157; P:lipoprotein metabolic process; IEA:Ensembl. DR GO; GO:0001889; P:liver development; ISS:HGNC-UCL. DR GO; GO:0032802; P:low-density lipoprotein particle receptor catabolic process; IDA:UniProtKB. DR GO; GO:0007041; P:lysosomal transport; IDA:BHF-UCL. DR GO; GO:0010989; P:negative regulation of low-density lipoprotein particle clearance; IDA:BHF-UCL. DR GO; GO:1905596; P:negative regulation of low-density lipoprotein particle receptor binding; IDA:BHF-UCL. DR GO; GO:1905598; P:negative regulation of low-density lipoprotein receptor activity; IDA:BHF-UCL. DR GO; GO:0002091; P:negative regulation of receptor internalization; IDA:ComplexPortal. DR GO; GO:0001920; P:negative regulation of receptor recycling; IDA:BHF-UCL. DR GO; GO:1905601; P:negative regulation of receptor-mediated endocytosis involved in cholesterol transport; IDA:BHF-UCL. DR GO; GO:2000650; P:negative regulation of sodium ion transmembrane transporter activity; IDA:BHF-UCL. DR GO; GO:0022008; P:neurogenesis; ISS:HGNC-UCL. DR GO; GO:0030182; P:neuron differentiation; ISS:HGNC-UCL. DR GO; GO:0006644; P:phospholipid metabolic process; IEA:Ensembl. DR GO; GO:0032805; P:positive regulation of low-density lipoprotein particle receptor catabolic process; IDA:BHF-UCL. DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IMP:HGNC-UCL. DR GO; GO:0002092; P:positive regulation of receptor internalization; IDA:BHF-UCL. DR GO; GO:0016540; P:protein autoprocessing; IDA:HGNC-UCL. DR GO; GO:0043523; P:regulation of neuron apoptotic process; ISS:UniProtKB. DR GO; GO:0010469; P:regulation of signaling receptor activity; IDA:BHF-UCL. DR GO; GO:0006641; P:triglyceride metabolic process; IEA:Ensembl. DR CDD; cd16839; PCSK9_C-CRD; 1. DR CDD; cd04077; Peptidases_S8_PCSK9_ProteinaseK_like; 1. DR DisProt; DP02551; -. DR Gene3D; 3.30.70.80; Peptidase S8 propeptide/proteinase inhibitor I9; 1. DR Gene3D; 3.40.50.200; Peptidase S8/S53 domain; 1. DR Gene3D; 2.60.120.690; Proprotein convertase subtilisin/kexin type 9; 1. DR InterPro; IPR041254; PCSK9_C1. DR InterPro; IPR041052; PCSK9_C2. DR InterPro; IPR041051; PCSK9_C3. DR InterPro; IPR034193; PCSK9_ProteinaseK-like. DR InterPro; IPR000209; Peptidase_S8/S53_dom. DR InterPro; IPR036852; Peptidase_S8/S53_dom_sf. DR InterPro; IPR015500; Peptidase_S8_subtilisin-rel. DR InterPro; IPR010259; S8pro/Inhibitor_I9. DR InterPro; IPR037045; S8pro/Inhibitor_I9_sf. DR PANTHER; PTHR43806; PEPTIDASE S8; 1. DR PANTHER; PTHR43806:SF60; PROPROTEIN CONVERTASE SUBTILISIN_KEXIN TYPE 9; 1. DR Pfam; PF05922; Inhibitor_I9; 1. DR Pfam; PF18459; PCSK9_C1; 1. DR Pfam; PF18464; PCSK9_C2; 1. DR Pfam; PF18463; PCSK9_C3; 1. DR Pfam; PF00082; Peptidase_S8; 1. DR PRINTS; PR00723; SUBTILISIN. DR SUPFAM; SSF54897; Protease propeptides/inhibitors; 1. DR SUPFAM; SSF52743; Subtilisin-like; 1. DR PROSITE; PS51892; SUBTILASE; 1. DR Genevisible; Q8NBP7; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Apoptosis; Autocatalytic cleavage; KW Calcium; Cholesterol metabolism; Cytoplasm; Direct protein sequencing; KW Disease variant; Disulfide bond; Endoplasmic reticulum; Endosome; KW Glycoprotein; Golgi apparatus; Hydrolase; Lipid metabolism; Lysosome; KW Phosphoprotein; Protease; Reference proteome; Secreted; Serine protease; KW Signal; Steroid metabolism; Sterol metabolism; Sulfation; Zymogen. FT SIGNAL 1..30 FT /evidence="ECO:0000269|PubMed:12552133" FT PROPEP 31..152 FT /evidence="ECO:0000269|PubMed:12552133" FT /id="PRO_0000027120" FT CHAIN 153..692 FT /note="Proprotein convertase subtilisin/kexin type 9" FT /id="PRO_0000027121" FT DOMAIN 77..149 FT /note="Inhibitor I9" FT /evidence="ECO:0000255" FT DOMAIN 155..461 FT /note="Peptidase S8" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240" FT REGION 450..692 FT /note="C-terminal domain" FT ACT_SITE 186 FT /note="Charge relay system" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240" FT ACT_SITE 226 FT /note="Charge relay system" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240" FT ACT_SITE 386 FT /note="Charge relay system" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240" FT SITE 152..153 FT /note="Cleavage; by autolysis" FT /evidence="ECO:0000269|PubMed:14622975" FT SITE 218..219 FT /note="Cleavage; by furin and PCSK5" FT /evidence="ECO:0000269|PubMed:16912035" FT MOD_RES 38 FT /note="Sulfotyrosine" FT /evidence="ECO:0000269|PubMed:16912035" FT MOD_RES 47 FT /note="Phosphoserine; by FAM20C" FT /evidence="ECO:0000269|PubMed:18498363, FT ECO:0000269|PubMed:26091039" FT MOD_RES 688 FT /note="Phosphoserine; by FAM20C" FT /evidence="ECO:0000269|PubMed:18498363, FT ECO:0000269|PubMed:26091039, ECO:0007744|PubMed:17081983, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT CARBOHYD 533 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16912035" FT DISULFID 223..255 FT /evidence="ECO:0000255" FT DISULFID 323..358 FT /evidence="ECO:0000255" FT DISULFID 457..527 FT /evidence="ECO:0000255" FT DISULFID 477..526 FT /evidence="ECO:0000255" FT DISULFID 486..509 FT /evidence="ECO:0000255" FT DISULFID 534..601 FT /evidence="ECO:0000255" FT DISULFID 552..600 FT /evidence="ECO:0000255" FT DISULFID 562..588 FT /evidence="ECO:0000255" FT DISULFID 608..679 FT /evidence="ECO:0000255" FT DISULFID 626..678 FT /evidence="ECO:0000255" FT DISULFID 635..654 FT /evidence="ECO:0000255" FT VAR_SEQ 1..174 FT /note="MGTVSSRRSWWPLPLLLLLLLLLGPAGARAQEDEDGDYEELVLALRSEEDGL FT AEAPEHGTTATFHRCAKDPWRLPGTYVVVLKEETHLSQSERTARRLQAQAARRGYLTKI FT LHVFHGLLPGFLVKMSGDLLELALKLPHVDYIEEDSSVFAQSIPWNLERITPPRYRADE FT YQPP -> MSPWK (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_008844" FT VAR_SEQ 333..365 FT /note="VITVGATNAQDQPVTLGTLGTNFGRCVDLFAPG -> GRTSLVPPATAAPAL FT CHRVGHHRLLPTWLALQP (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_008845" FT VAR_SEQ 366..692 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_008846" FT VARIANT 23 FT /note="L -> LL (this variant seems to have a modifier FT effect on LDLR mutation and familial hypercholesterolemia)" FT /evidence="ECO:0000269|PubMed:19319977, FT ECO:0000269|PubMed:22095935, ECO:0000269|Ref.4, FT ECO:0000269|Ref.5" FT /id="VAR_021336" FT VARIANT 46 FT /note="R -> L (correlated with lower plasma levels of FT low-density lipoprotein cholesterol; reduced FT phosphorylation at Ser-47; dbSNP:rs11591147)" FT /evidence="ECO:0000269|PubMed:12730697, FT ECO:0000269|PubMed:16465619, ECO:0000269|PubMed:22095935, FT ECO:0000269|Ref.4" FT /id="VAR_017197" FT VARIANT 53 FT /note="A -> V (reduced phosphorylation at Ser-47; FT dbSNP:rs11583680)" FT /evidence="ECO:0000269|PubMed:12730697, FT ECO:0000269|PubMed:16465619, ECO:0000269|PubMed:22095935, FT ECO:0000269|Ref.4" FT /id="VAR_017198" FT VARIANT 57 FT /note="E -> K (in dbSNP:rs145886902)" FT /evidence="ECO:0000269|PubMed:16465619" FT /id="VAR_025451" FT VARIANT 77 FT /note="T -> I (in dbSNP:rs756060557)" FT /id="VAR_058520" FT VARIANT 93 FT /note="R -> C (in dbSNP:rs151193009)" FT /id="VAR_058521" FT VARIANT 106 FT /note="G -> R" FT /id="VAR_058522" FT VARIANT 114 FT /note="V -> A (in dbSNP:rs775988212)" FT /id="VAR_058523" FT VARIANT 127 FT /note="S -> R (in FHCL3; dbSNP:rs28942111)" FT /evidence="ECO:0000269|PubMed:12730697" FT /id="VAR_017199" FT VARIANT 129 FT /note="D -> G (in FHCL3; dbSNP:rs1553135971)" FT /id="VAR_058524" FT VARIANT 157 FT /note="N -> K (in dbSNP:rs143117125)" FT /id="VAR_058525" FT VARIANT 174 FT /note="P -> S (found in patients with familial FT hypercholesterolemia carrying a homozygous LDLR mutation; FT acts as a disease modifier resulting in a mild phenotype; FT dbSNP:rs533273863)" FT /evidence="ECO:0000269|PubMed:22417841" FT /id="VAR_067351" FT VARIANT 215 FT /note="R -> H (in FHCL3; dbSNP:rs794728683)" FT /id="VAR_058526" FT VARIANT 216 FT /note="F -> L (in FHCL3; partial loss of cleavage by furin FT and PCSK5; dbSNP:rs28942112)" FT /evidence="ECO:0000269|PubMed:12730697" FT /id="VAR_017200" FT VARIANT 218 FT /note="R -> S (in FHCL3; complete loss of cleavage by furin FT and PCSK5; reduces glycosylation levels; no effect on FT protein sulfation and phosphorylation; no effect on protein FT sulfation but inhibits phosphorylation when associated with FT Y-374; highly reduces LDL uptake when associated with FT Y-374; dbSNP:rs970575319)" FT /evidence="ECO:0000269|PubMed:18799458, FT ECO:0000269|PubMed:24808179" FT /id="VAR_058527" FT VARIANT 219 FT /note="Q -> E (in dbSNP:rs778617372)" FT /id="VAR_058528" FT VARIANT 237 FT /note="R -> W (in dbSNP:rs148195424)" FT /evidence="ECO:0000269|PubMed:16465619" FT /id="VAR_025452" FT VARIANT 239 FT /note="A -> D" FT /id="VAR_058529" FT VARIANT 253 FT /note="L -> F (correlated with lower plasma levels of FT low-density lipoprotein cholesterol; dbSNP:rs72646508)" FT /evidence="ECO:0000269|PubMed:16465619" FT /id="VAR_025453" FT VARIANT 357 FT /note="R -> H (in FHCL3; dbSNP:rs370507566)" FT /id="VAR_058530" FT VARIANT 374 FT /note="D -> H (in FHCL3; dbSNP:rs137852912)" FT /id="VAR_058531" FT VARIANT 374 FT /note="D -> Y (in FHCL3; partial loss of cleavage by furin FT and PCSK5; no effect on protein sulfation but inhibits FT phosphorylation when associated with S-218; highly FT increases LDL uptake when associated with S-218; FT dbSNP:rs137852912)" FT /evidence="ECO:0000269|PubMed:18799458, FT ECO:0000269|PubMed:24808179" FT /id="VAR_058532" FT VARIANT 391 FT /note="H -> N (in dbSNP:rs146471967)" FT /evidence="ECO:0000269|PubMed:16465619" FT /id="VAR_025454" FT VARIANT 394 FT /note="G -> S (in FHCL3; uncertain significance; FT dbSNP:rs368257906)" FT /evidence="ECO:0000269|PubMed:22095935" FT /id="VAR_067282" FT VARIANT 417 FT /note="H -> Q (in dbSNP:rs143275858)" FT /evidence="ECO:0000269|PubMed:16465619" FT /id="VAR_025455" FT VARIANT 425 FT /note="N -> S (in dbSNP:rs28362261)" FT /evidence="ECO:0000269|PubMed:16465619, ECO:0000269|Ref.4" FT /id="VAR_021337" FT VARIANT 443 FT /note="A -> T (correlated with lower plasma levels of FT low-density lipoprotein cholesterol; more extensive FT cleavage by furin and PCSK5; dbSNP:rs28362263)" FT /evidence="ECO:0000269|PubMed:16465619, ECO:0000269|Ref.4" FT /id="VAR_021338" FT VARIANT 452 FT /note="G -> D" FT /id="VAR_058533" FT VARIANT 469 FT /note="R -> W (in dbSNP:rs141502002)" FT /evidence="ECO:0000269|PubMed:16465619" FT /id="VAR_025456" FT VARIANT 474 FT /note="V -> I (in dbSNP:rs562556)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:16465619, ECO:0000269|PubMed:17971861, FT ECO:0000269|PubMed:22095935, ECO:0000269|Ref.1, FT ECO:0000269|Ref.4, ECO:0000269|Ref.5, ECO:0000269|Ref.7" FT /id="VAR_021339" FT VARIANT 482 FT /note="E -> G (in dbSNP:rs141995194)" FT /evidence="ECO:0000269|PubMed:16465619" FT /id="VAR_025457" FT VARIANT 482 FT /note="E -> Q (no effect on interaction with ANXA2)" FT /evidence="ECO:0000269|PubMed:24808179" FT /id="VAR_073657" FT VARIANT 496 FT /note="R -> W (in FHCL3; dbSNP:rs374603772)" FT /id="VAR_058534" FT VARIANT 515 FT /note="F -> L (in dbSNP:rs1356131564)" FT /evidence="ECO:0000269|PubMed:16465619" FT /id="VAR_025458" FT VARIANT 522 FT /note="A -> T (in dbSNP:rs777300852)" FT /id="VAR_058535" FT VARIANT 553 FT /note="H -> R (in dbSNP:rs28362270)" FT /evidence="ECO:0000269|PubMed:16465619, ECO:0000269|Ref.4" FT /id="VAR_021340" FT VARIANT 554 FT /note="Q -> E (increases interaction with ANXA2; FT dbSNP:rs149311926)" FT /evidence="ECO:0000269|PubMed:16465619, FT ECO:0000269|PubMed:18799458" FT /id="VAR_025459" FT VARIANT 616 FT /note="P -> L (in dbSNP:rs755750316)" FT /id="VAR_058536" FT VARIANT 619 FT /note="Q -> P (in dbSNP:rs28362277)" FT /evidence="ECO:0000269|PubMed:16465619, ECO:0000269|Ref.4" FT /id="VAR_021341" FT VARIANT 668 FT /note="S -> R (in dbSNP:rs762298323)" FT /id="VAR_058537" FT VARIANT 670 FT /note="G -> E (in dbSNP:rs505151)" FT /evidence="ECO:0000269|PubMed:12730697, FT ECO:0000269|PubMed:16465619, ECO:0000269|PubMed:17971861, FT ECO:0000269|PubMed:22095935, ECO:0000269|Ref.1, FT ECO:0000269|Ref.4, ECO:0000269|Ref.5, ECO:0000269|Ref.7" FT /id="VAR_017201" FT MUTAGEN 67 FT /note="C->A: Does not affect multimerization or zymogen FT processing." FT /evidence="ECO:0000269|PubMed:12552133" FT MUTAGEN 226 FT /note="H->A: Remains in the endoplasmic reticulum and is FT not secreted." FT /evidence="ECO:0000269|PubMed:12552133" FT MUTAGEN 533 FT /note="N->A: 1.5 kDa decrease of the apparent molecular FT mass of pro-PCSK9 and PCSK9 and no effect on processing and FT secretion." FT /evidence="ECO:0000269|PubMed:12552133" FT CONFLICT 423 FT /note="V -> A (in Ref. 3; BAC11572)" FT /evidence="ECO:0000305" FT STRAND 34..36 FT /evidence="ECO:0007829|PDB:6MV5" FT HELIX 37..45 FT /evidence="ECO:0007829|PDB:6MV5" FT STRAND 63..65 FT /evidence="ECO:0007829|PDB:6U26" FT HELIX 70..72 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 73..82 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 84..86 FT /evidence="ECO:0007829|PDB:4OV6" FT HELIX 88..104 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 110..115 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 117..119 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 121..125 FT /evidence="ECO:0007829|PDB:6U26" FT HELIX 128..130 FT /evidence="ECO:0007829|PDB:6U26" FT HELIX 131..135 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 140..151 FT /evidence="ECO:0007829|PDB:6U26" FT HELIX 156..160 FT /evidence="ECO:0007829|PDB:6U26" FT HELIX 168..170 FT /evidence="ECO:0007829|PDB:3BPS" FT STRAND 180..187 FT /evidence="ECO:0007829|PDB:6U26" FT TURN 194..199 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 200..206 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 212..214 FT /evidence="ECO:0007829|PDB:4NMX" FT TURN 218..220 FT /evidence="ECO:0007829|PDB:3H42" FT TURN 221..224 FT /evidence="ECO:0007829|PDB:6U26" FT HELIX 225..235 FT /evidence="ECO:0007829|PDB:6U26" FT TURN 237..239 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 241..244 FT /evidence="ECO:0007829|PDB:2P4E" FT STRAND 246..251 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 257..260 FT /evidence="ECO:0007829|PDB:6U26" FT HELIX 261..277 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 283..287 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 289..292 FT /evidence="ECO:0007829|PDB:6U26" FT HELIX 295..306 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 310..314 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 317..321 FT /evidence="ECO:0007829|PDB:6U26" FT HELIX 322..324 FT /evidence="ECO:0007829|PDB:6U26" FT TURN 327..329 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 333..339 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 343..345 FT /evidence="ECO:0007829|PDB:2PMW" FT STRAND 349..352 FT /evidence="ECO:0007829|PDB:2W2Q" FT STRAND 355..358 FT /evidence="ECO:0007829|PDB:3P5B" FT STRAND 361..364 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 366..371 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 373..375 FT /evidence="ECO:0007829|PDB:5VLL" FT STRAND 379..382 FT /evidence="ECO:0007829|PDB:6U26" FT HELIX 385..402 FT /evidence="ECO:0007829|PDB:6U26" FT HELIX 408..418 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 419..422 FT /evidence="ECO:0007829|PDB:6U26" FT HELIX 426..428 FT /evidence="ECO:0007829|PDB:6U26" FT HELIX 431..433 FT /evidence="ECO:0007829|PDB:6U26" FT TURN 434..436 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 440..442 FT /evidence="ECO:0007829|PDB:3P5B" FT STRAND 457..461 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 469..471 FT /evidence="ECO:0007829|PDB:6U3X" FT STRAND 472..475 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 482..489 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 491..493 FT /evidence="ECO:0007829|PDB:3GCX" FT STRAND 495..501 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 508..513 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 515..517 FT /evidence="ECO:0007829|PDB:5OCA" FT STRAND 521..527 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 535..539 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 544..546 FT /evidence="ECO:0007829|PDB:2QTW" FT STRAND 549..551 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 554..556 FT /evidence="ECO:0007829|PDB:5VL7" FT STRAND 557..565 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 568..570 FT /evidence="ECO:0007829|PDB:2P4E" FT STRAND 587..589 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 594..602 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 606..615 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 621..625 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 631..637 FT /evidence="ECO:0007829|PDB:6U26" FT TURN 641..643 FT /evidence="ECO:0007829|PDB:6U3I" FT STRAND 644..650 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 653..658 FT /evidence="ECO:0007829|PDB:6U26" FT STRAND 672..681 FT /evidence="ECO:0007829|PDB:6U26" SQ SEQUENCE 692 AA; 74286 MW; 9BCB9418B90AEE23 CRC64; MGTVSSRRSW WPLPLLLLLL LLLGPAGARA QEDEDGDYEE LVLALRSEED GLAEAPEHGT TATFHRCAKD PWRLPGTYVV VLKEETHLSQ SERTARRLQA QAARRGYLTK ILHVFHGLLP GFLVKMSGDL LELALKLPHV DYIEEDSSVF AQSIPWNLER ITPPRYRADE YQPPDGGSLV EVYLLDTSIQ SDHREIEGRV MVTDFENVPE EDGTRFHRQA SKCDSHGTHL AGVVSGRDAG VAKGASMRSL RVLNCQGKGT VSGTLIGLEF IRKSQLVQPV GPLVVLLPLA GGYSRVLNAA CQRLARAGVV LVTAAGNFRD DACLYSPASA PEVITVGATN AQDQPVTLGT LGTNFGRCVD LFAPGEDIIG ASSDCSTCFV SQSGTSQAAA HVAGIAAMML SAEPELTLAE LRQRLIHFSA KDVINEAWFP EDQRVLTPNL VAALPPSTHG AGWQLFCRTV WSAHSGPTRM ATAVARCAPD EELLSCSSFS RSGKRRGERM EAQGGKLVCR AHNAFGGEGV YAIARCCLLP QANCSVHTAP PAEASMGTRV HCHQQGHVLT GCSSHWEVED LGTHKPPVLR PRGQPNQCVG HREASIHASC CHAPGLECKV KEHGIPAPQE QVTVACEEGW TLTGCSALPG TSHVLGAYAV DNTCVVRSRD VSTTGSTSEG AVTAVAICCR SRHLAQASQE LQ //