PCSK9_HUMAN
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 03-AUG-2022, entry version 200.
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, AND VARIANTS LEU-23 INS; LEU-46; VAL-53; SER-394; ILE-474 AND
RP 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:24808179}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC 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/";
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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; 137.
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 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; Q8NBP7; -.
DR PeptideAtlas; Q8NBP7; -.
DR PRIDE; Q8NBP7; -.
DR ProteomicsDB; 72807; -. [Q8NBP7-1]
DR ProteomicsDB; 72808; -. [Q8NBP7-2]
DR ABCD; Q8NBP7; 98 sequenced antibodies.
DR Antibodypedia; 33231; 739 antibodies from 43 providers.
DR DNASU; 255738; -.
DR Ensembl; ENST00000302118.5; ENSP00000303208.5; ENSG00000169174.11. [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 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; CNKAAWR; -.
DR OrthoDB; 921536at2759; -.
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; 36 hits in 1078 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 115 other tissues.
DR ExpressionAtlas; Q8NBP7; baseline and differential.
DR Genevisible; Q8NBP7; HS.
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:0005791; C:rough endoplasmic reticulum; IEA:Ensembl.
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; cd04077; Peptidases_S8_PCSK9_ProteinaseK_like; 1.
DR DisProt; DP02551; -.
DR Gene3D; 3.30.70.80; -; 1.
DR Gene3D; 3.40.50.200; -; 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 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; SSF52743; SSF52743; 1.
DR PROSITE; PS51892; SUBTILASE; 1.
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 (associated with lower plasma levels of low-
FT density lipoprotein cholesterol; reduced phosphorylation at
FT 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 (associated with reduced phosphorylation at
FT Ser-47; 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 Y-
FT 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 (associated with lower plasma levels of low-
FT 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 (found in a patient associated with autosomal
FT dominant hypercholesterolemia; unknown pathological
FT significance; 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 (associated with lower plasma levels of low-
FT density lipoprotein cholesterol; more extensive cleavage by
FT 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
