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Proprotein convertase subtilisin/kexin type 9 (EC 3.4.21.-) (Neural apoptosis-regulated convertase 1) (NARC-1) (Proprotein convertase 9) (PC9) (Subtilisin/kexin-like protease PC9)

 PCSK9_HUMAN             Reviewed;         692 AA.
Q8NBP7; A8T640; C0JYY9; Q5PSM5; Q5SZQ2;
07-NOV-2003, integrated into UniProtKB/Swiss-Prot.
11-JAN-2011, sequence version 3.
22-NOV-2017, entry version 166.
RecName: Full=Proprotein convertase subtilisin/kexin type 9;
EC=3.4.21.-;
AltName: Full=Neural apoptosis-regulated convertase 1;
Short=NARC-1;
AltName: Full=Proprotein convertase 9;
Short=PC9;
AltName: Full=Subtilisin/kexin-like protease PC9;
Flags: Precursor;
Name=PCSK9; Synonyms=NARC1; ORFNames=PSEC0052;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS ILE-474 AND
GLU-670.
Chiang L.W.;
"Nucleic acid molecules derived from rat brain and programmed cell
death models.";
Patent number WO0131007, 03-MAY-2001.
[2]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS ILE-474 AND
GLU-670.
PubMed=17971861; DOI=10.1371/journal.pone.0001098;
Ding K., McDonough S.J., Kullo I.J.;
"Evidence for positive selection in the C-terminal domain of the
cholesterol metabolism gene PCSK9 based on phylogenetic analysis in 14
primate species.";
PLoS ONE 2:E1098-E1098(2007).
[3]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
ILE-474.
TISSUE=Cerebellum, and Teratocarcinoma;
PubMed=14702039; DOI=10.1038/ng1285;
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
"Complete sequencing and characterization of 21,243 full-length human
cDNAs.";
Nat. Genet. 36:40-45(2004).
[4]
NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LEU-23 INS; LEU-46;
VAL-53; SER-425; THR-443; ILE-474; ARG-553; PRO-619 AND GLU-670.
SeattleSNPs variation discovery resource;
Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
[5]
NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LEU-23 INS; ILE-474
AND GLU-670.
NHLBI resequencing and genotyping service (RS&G);
Submitted (DEC-2008) to the EMBL/GenBank/DDBJ databases.
[6]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=16710414; DOI=10.1038/nature04727;
Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
Beck S., Rogers J., Bentley D.R.;
"The DNA sequence and biological annotation of human chromosome 1.";
Nature 441:315-321(2006).
[7]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANTS ILE-474
AND GLU-670.
Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
Venter J.C.;
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
[8]
PROTEIN SEQUENCE OF N-TERMINUS, CHARACTERIZATION, AND MUTAGENESIS OF
CYS-67; HIS-226 AND ASN-533.
PubMed=12552133; DOI=10.1073/pnas.0335507100;
Seidah N.G., Benjannet S., Wickham L., Marcinkiewicz J., Jasmin S.B.,
Stifani S., Basak A., Prat A., Chretien M.;
"The secretory proprotein convertase neural apoptosis-regulated
convertase 1 (NARC-1): liver regeneration and neuronal
differentiation.";
Proc. Natl. Acad. Sci. U.S.A. 100:928-933(2003).
[9]
AUTOCATALYTIC CLEAVAGE SITE.
PubMed=14622975; DOI=10.1016/j.abb.2003.09.011;
Naureckiene S., Ma L., Sreekumar K., Purandare U., Lo C.F., Huang Y.,
Chiang L.W., Grenier J.M., Ozenberger B.A., Jacobsen J.S.,
Kennedy J.D., DiStefano P.S., Wood A., Bingham B.;
"Functional characterization of Narc 1, a novel proteinase related to
proteinase K.";
Arch. Biochem. Biophys. 420:55-67(2003).
[10]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-688, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
Mann M.;
"Global, in vivo, and site-specific phosphorylation dynamics in
signaling networks.";
Cell 127:635-648(2006).
[11]
GLYCOSYLATION AT ASN-533, SULFATION AT TYR-38, AND CLEAVAGE AT ARG-218
BY FURIN AND PCSK5.
PubMed=16912035; DOI=10.1074/jbc.M606495200;
Benjannet S., Rhainds D., Hamelin J., Nassoury N., Seidah N.G.;
"The proprotein convertase (PC) PCSK9 is inactivated by furin and/or
PC5/6A: functional consequences of natural mutations and post-
translational modifications.";
J. Biol. Chem. 281:30561-30572(2006).
[12]
FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH LDLR.
PubMed=17461796; DOI=10.1111/j.1600-0854.2007.00562.x;
Nassoury N., Blasiole D.A., Tebon Oler A., Benjannet S., Hamelin J.,
Poupon V., McPherson P.S., Attie A.D., Prat A., Seidah N.G.;
"The cellular trafficking of the secretory proprotein convertase PCSK9
and its dependence on the LDLR.";
Traffic 8:718-732(2007).
[13]
FUNCTION, AND SUBUNIT.
PubMed=18197702; DOI=10.1021/bi7016359;
Fan D., Yancey P.G., Qiu S., Ding L., Weeber E.J., Linton M.F.,
Fazio S.;
"Self-association of human PCSK9 correlates with its LDLR-degrading
activity.";
Biochemistry 47:1631-1639(2008).
[14]
FUNCTION, AND INTERACTION WITH BACE1.
PubMed=18660751; DOI=10.1038/embor.2008.132;
Jonas M.C., Costantini C., Puglielli L.;
"PCSK9 is required for the disposal of non-acetylated intermediates of
the nascent membrane protein BACE1.";
EMBO Rep. 9:916-922(2008).
[15]
PHOSPHORYLATION AT SER-47 AND SER-688, AND IDENTIFICATION BY MASS
SPECTROMETRY.
PubMed=18498363; DOI=10.1111/j.1742-4658.2008.06495.x;
Dewpura T., Raymond A., Hamelin J., Seidah N.G., Mbikay M.,
Chretien M., Mayne J.;
"PCSK9 is phosphorylated by a Golgi casein kinase-like kinase ex vivo
and circulates as a phosphoprotein in humans.";
FEBS J. 275:3480-3493(2008).
[16]
FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH VLDLR AND
LRP8/APOER2.
PubMed=18039658; DOI=10.1074/jbc.M708098200;
Poirier S., Mayer G., Benjannet S., Bergeron E., Marcinkiewicz J.,
Nassoury N., Mayer H., Nimpf J., Prat A., Seidah N.G.;
"The proprotein convertase PCSK9 induces the degradation of low
density lipoprotein receptor (LDLR) and its closest family members
VLDLR and ApoER2.";
J. Biol. Chem. 283:2363-2372(2008).
[17]
FUNCTION, INTERACTION WITH ANXA2, VARIANT HCHOLA3 TYR-374,
CHARACTERIZATION OF VARIANT HCHOLA3 TYR-374, VARIANT GLU-554, AND
CHARACTERIZATION OF VARIANT GLU-554.
PubMed=18799458; DOI=10.1074/jbc.M805971200;
Mayer G., Poirier S., Seidah N.G.;
"Annexin A2 is a C-terminal PCSK9-binding protein that regulates
endogenous low density lipoprotein receptor levels.";
J. Biol. Chem. 283:31791-31801(2008).
[18]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
PubMed=18669648; DOI=10.1073/pnas.0805139105;
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
Elledge S.J., Gygi S.P.;
"A quantitative atlas of mitotic phosphorylation.";
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
[19]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-688, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
PubMed=20068231; DOI=10.1126/scisignal.2000475;
Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
Mann M.;
"Quantitative phosphoproteomics reveals widespread full
phosphorylation site occupancy during mitosis.";
Sci. Signal. 3:RA3-RA3(2010).
[20]
FUNCTION.
PubMed=22074827; DOI=10.1016/j.bbrc.2011.10.110;
Chen Y., Wang H., Yu L., Yu X., Qian Y.W., Cao G., Wang J.;
"Role of ubiquitination in PCSK9-mediated low-density lipoprotein
receptor degradation.";
Biochem. Biophys. Res. Commun. 415:515-518(2011).
[21]
INTERACTION WITH LDLR.
PubMed=21149300; DOI=10.1074/jbc.M110.199042;
Yamamoto T., Lu C., Ryan R.O.;
"A two-step binding model of PCSK9 interaction with the low density
lipoprotein receptor.";
J. Biol. Chem. 286:5464-5470(2011).
[22]
DOMAIN C-TERMINAL.
PubMed=22027821; DOI=10.1074/jbc.M111.273474;
Du F., Hui Y., Zhang M., Linton M.F., Fazio S., Fan D.;
"Novel domain interaction regulates secretion of proprotein convertase
subtilisin/kexin type 9 (PCSK9) protein.";
J. Biol. Chem. 286:43054-43061(2011).
[23]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-688, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21406692; DOI=10.1126/scisignal.2001570;
Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
Blagoev B.;
"System-wide temporal characterization of the proteome and
phosphoproteome of human embryonic stem cell differentiation.";
Sci. Signal. 4:RS3-RS3(2011).
[24]
FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH APOB.
PubMed=22580899; DOI=10.1161/ATVBAHA.112.250043;
Sun H., Samarghandi A., Zhang N., Yao Z., Xiong M., Teng B.B.;
"Proprotein convertase subtilisin/kexin type 9 interacts with
apolipoprotein B and prevents its intracellular degradation,
irrespective of the low-density lipoprotein receptor.";
Arterioscler. Thromb. Vasc. Biol. 32:1585-1595(2012).
[25]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-688, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma, and Erythroleukemia;
PubMed=23186163; DOI=10.1021/pr300630k;
Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
Mohammed S.;
"Toward a comprehensive characterization of a human cancer cell
phosphoproteome.";
J. Proteome Res. 12:260-271(2013).
[26]
PHOSPHORYLATION AT SER-47 AND SER-688.
PubMed=26091039; DOI=10.1016/j.cell.2015.05.028;
Tagliabracci V.S., Wiley S.E., Guo X., Kinch L.N., Durrant E., Wen J.,
Xiao J., Cui J., Nguyen K.B., Engel J.L., Coon J.J., Grishin N.,
Pinna L.A., Pagliarini D.J., Dixon J.E.;
"A single kinase generates the majority of the secreted
phosphoproteome.";
Cell 161:1619-1632(2015).
[27]
REVIEW.
PubMed=18280815; DOI=10.1016/j.bbalip.2008.01.003;
Lopez D.;
"PCSK9: an enigmatic protease.";
Biochim. Biophys. Acta 1781:184-191(2008).
[28]
REVIEW.
PubMed=18649882; DOI=10.1016/j.atherosclerosis.2008.06.010;
Lambert G., Charlton F., Rye K.A., Piper D.E.;
"Molecular basis of PCSK9 function.";
Atherosclerosis 203:1-7(2009).
[29]
REVIEW.
PubMed=19930098; DOI=10.1111/j.1365-2796.2009.02167.x;
Mousavi S.A., Berge K.E., Leren T.P.;
"The unique role of proprotein convertase subtilisin/kexin 9 in
cholesterol homeostasis.";
J. Intern. Med. 266:507-519(2009).
[30]
REVIEW.
PubMed=19020338; DOI=10.1194/jlr.R800091-JLR200;
Horton J.D., Cohen J.C., Hobbs H.H.;
"PCSK9: a convertase that coordinates LDL catabolism.";
J. Lipid Res. 50:S172-S177(2009).
[31]
REVIEW.
PubMed=21943799; DOI=10.1016/j.numecd.2011.06.002;
Tibolla G., Norata G.D., Artali R., Meneghetti F., Catapano A.L.;
"Proprotein convertase subtilisin/kexin type 9 (PCSK9): from
structure-function relation to therapeutic inhibition.";
Nutr. Metab. Cardiovasc. Dis. 21:835-843(2011).
[32]
REVIEW ON VARIANTS.
PubMed=19191301; DOI=10.1002/humu.20882;
Abifadel M., Rabes J.P., Devillers M., Munnich A., Erlich D.,
Junien C., Varret M., Boileau C.;
"Mutations and polymorphisms in the proprotein convertase subtilisin
kexin 9 (PCSK9) gene in cholesterol metabolism and disease.";
Hum. Mutat. 30:520-529(2009).
[33]
POLYMORPHISM, AND VARIANT SER-174.
PubMed=22417841; DOI=10.1016/j.atherosclerosis.2012.02.018;
Slimani A., Jelassi A., Jguirim I., Najah M., Rebhi L., Omezzine A.,
Maatouk F., Hamda K.B., Kacem M., Rabes J.P., Abifadel M., Boileau C.,
Rouis M., Slimane M.N., Varret M.;
"Effect of mutations in LDLR and PCSK9 genes on phenotypic variability
in Tunisian familial hypercholesterolemia patients.";
Atherosclerosis 222:158-166(2012).
[34]
FUNCTION, AND INTERACTION WITH SCNN1A; SCNN1B AND SCNN1G.
PubMed=22493497; DOI=10.1074/jbc.M112.363382;
Sharotri V., Collier D.M., Olson D.R., Zhou R., Snyder P.M.;
"Regulation of epithelial sodium channel trafficking by proprotein
convertase subtilisin/kexin type 9 (PCSK9).";
J. Biol. Chem. 287:19266-19274(2012).
[35]
FUNCTION, INTERACTION WITH ANXA2, VARIANT GLN-482, CHARACTERIZATION OF
VARIANT GLN-482, VARIANTS HCHOLA3 SER-218 AND TYR-374,
CHARACTERIZATION OF VARIANTS HCHOLA3 SER-218 AND TYR-374, SULFATION,
PHOSPHORYLATION, GLYCOSYLATION, AND SUBUNIT.
PubMed=24808179; DOI=10.1074/jbc.M113.541094;
Ly K., Saavedra Y.G., Canuel M., Routhier S., Desjardins R.,
Hamelin J., Mayne J., Lazure C., Seidah N.G., Day R.;
"Annexin A2 reduces PCSK9 protein levels via a translational mechanism
and interacts with the M1 and M2 domains of PCSK9.";
J. Biol. Chem. 289:17732-17746(2014).
[36]
X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 31-692.
PubMed=17502100; DOI=10.1016/j.str.2007.04.004;
Piper D.E., Jackson S., Liu Q., Romanow W.G., Shetterly S.,
Thibault S.T., Shan B., Walker N.P.;
"The crystal structure of PCSK9: a regulator of plasma LDL-
cholesterol.";
Structure 15:545-552(2007).
[37]
VARIANTS HCHOLA3 ARG-127 AND LEU-216, AND VARIANTS LEU-46; VAL-53 AND
GLU-670.
PubMed=12730697; DOI=10.1038/ng1161;
Abifadel M., Varret M., Rabes J.-P., Allard D., Ouguerram K.,
Devillers M., Cruaud C., Benjannet S., Wickham L., Erlich D.,
Derre A., Villeger L., Farnier M., Beucler I., Bruckert E.,
Chambaz J., Chanu B., Lecerf J.-M., Luc G., Moulin P., Weissenbach J.,
Prat A., Krempf M., Junien C., Seidah N.G., Boileau C.;
"Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.";
Nat. Genet. 34:154-156(2003).
[38]
VARIANTS LEU-46; VAL-53; LYS-57; TRP-237; PHE-253; ASN-391; GLN-417;
SER-425; THR-443; TRP-469; ILE-474; GLY-482; LEU-515; ARG-553;
GLU-554; PRO-619 AND GLU-670.
PubMed=16465619; DOI=10.1086/500615;
Kotowski I.K., Pertsemlidis A., Luke A., Cooper R.S., Vega G.L.,
Cohen J.C., Hobbs H.H.;
"A spectrum of PCSK9 alleles contributes to plasma levels of low-
density lipoprotein cholesterol.";
Am. J. Hum. Genet. 78:410-422(2006).
[39]
POLYMORPHISM, VARIANT LEU-23 INS, AND IMPACT ON FAMILIAL
HYPERCHOLESTEROLEMIA.
PubMed=19319977; DOI=10.1002/humu.21002;
Abifadel M., Rabes J.-P., Jambart S., Halaby G., Gannage-Yared M.-H.,
Sarkis A., Beaino G., Varret M., Salem N., Corbani S., Aydenian H.,
Junien C., Munnich A., Boileau C.;
"The molecular basis of familial hypercholesterolemia in Lebanon:
spectrum of LDLR mutations and role of PCSK9 as a modifier gene.";
Hum. Mutat. 30:E682-E691(2009).
[40]
POLYMORPHISM, AND VARIANTS LEU-23 INS; LEU-46; VAL-53; SER-394;
ILE-474 AND GLU-670.
PubMed=22095935; DOI=10.1002/humu.21660;
Huijgen R., Sjouke B., Vis K., de Randamie J.S., Defesche J.C.,
Kastelein J.J., Hovingh G.K., Fouchier S.W.;
"Genetic variation in APOB, PCSK9, and ANGPTL3 in carriers of
pathogenic autosomal dominant hypercholesterolemic mutations with
unexpected low LDL-Cl Levels.";
Hum. Mutat. 33:448-455(2012).
-!- FUNCTION: Crucial player in the regulation of plasma cholesterol
homeostasis. Binds to low-density lipid receptor family members:
low density lipoprotein receptor (LDLR), very low density
lipoprotein receptor (VLDLR), apolipoprotein E receptor
(LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and
promotes their degradation in intracellular acidic compartments
(PubMed:18039658). Acts via a non-proteolytic mechanism to enhance
the degradation of the hepatic LDLR through a clathrin
LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR
from endosomes to the cell surface or direct it to lysosomes for
degradation. Can induce ubiquitination of LDLR leading to its
subsequent degradation (PubMed:18799458, PubMed:17461796,
PubMed:18197702, PubMed:22074827). Inhibits intracellular
degradation of APOB via the autophagosome/lysosome pathway in a
LDLR-independent manner. Involved in the disposal of non-
acetylated intermediates of BACE1 in the early secretory pathway
(PubMed:18660751). Inhibits epithelial Na(+) channel (ENaC)-
mediated Na(+) absorption by reducing ENaC surface expression
primarily by increasing its proteasomal degradation. Regulates
neuronal apoptosis via modulation of LRP8/APOER2 levels and
related anti-apoptotic signaling pathways.
{ECO:0000269|PubMed:17461796, ECO:0000269|PubMed:18039658,
ECO:0000269|PubMed:18197702, ECO:0000269|PubMed:18660751,
ECO:0000269|PubMed:18799458, ECO:0000269|PubMed:22074827,
ECO:0000269|PubMed:22493497, ECO:0000269|PubMed:22580899}.
-!- COFACTOR:
Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000305};
-!- ENZYME REGULATION: Its proteolytic activity is autoinhibited by
the non-covalent binding of the propeptide to the catalytic
domain. Inhibited by EGTA.
-!- SUBUNIT: Monomer. Can self-associate to form dimers and higher
multimers which may have increased LDLR degrading activity. The
precursor protein but not the mature protein may form multimers.
Interacts with APOB, VLDLR, LRP8/APOER2 and BACE1. The full-length
immature form (pro-PCSK9) interacts with SCNN1A, SCNN1B and
SCNN1G. The pro-PCSK9 form (via C-terminal domain) interacts with
LDLR. Interacts (via the C-terminal domain) with ANXA2 (via repeat
Annexin 1); the interaction inhibits the degradation of LDLR
(PubMed:18799458). {ECO:0000269|PubMed:17461796,
ECO:0000269|PubMed:18039658, ECO:0000269|PubMed:18197702,
ECO:0000269|PubMed:18660751, ECO:0000269|PubMed:18799458,
ECO:0000269|PubMed:21149300, ECO:0000269|PubMed:22493497,
ECO:0000269|PubMed:22580899, ECO:0000269|PubMed:24808179}.
-!- INTERACTION:
P07355:ANXA2; NbExp=7; IntAct=EBI-7539251, EBI-352622;
P01130:LDLR; NbExp=10; IntAct=EBI-7539251, EBI-988319;
P08253:MMP2; NbExp=4; IntAct=EBI-7539251, EBI-1033518;
-!- SUBCELLULAR LOCATION: Cytoplasm. Secreted. Endosome. Lysosome.
Cell surface. Endoplasmic reticulum. Golgi apparatus.
Note=Autocatalytic cleavage is required to transport it from the
endoplasmic reticulum to the Golgi apparatus and for the secretion
of the mature protein. Localizes to the endoplasmic reticulum in
the absence of LDLR and colocalizes to the cell surface and to the
endosomes/lysosomes in the presence of LDLR. The sorting to the
cell surface and endosomes is required in order to fully promote
LDLR degradation.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=2;
Name=1;
IsoId=Q8NBP7-1; Sequence=Displayed;
Name=2;
IsoId=Q8NBP7-2; Sequence=VSP_008844, VSP_008845, VSP_008846;
Note=No experimental confirmation available.;
-!- TISSUE SPECIFICITY: Expressed in neuro-epithelioma, colon
carcinoma, hepatic and pancreatic cell lines, and in Schwann
cells.
-!- DOMAIN: The C-terminal domain (CRD) is essential for the LDLR-
binding and degrading activities. {ECO:0000269|PubMed:22027821}.
-!- DOMAIN: The catalytic domain is responsible for mediating its
self-association. {ECO:0000269|PubMed:22027821}.
-!- PTM: Cleavage by furin and PCSK5 generates a truncated inactive
protein that is unable to induce LDLR degradation.
-!- PTM: Undergoes autocatalytic cleavage in the endoplasmic reticulum
to release the propeptide from the N-terminus and the cleavage of
the propeptide is strictly required for its maturation and
activation. The cleaved propeptide however remains associated with
the catalytic domain through non-covalent interactions, preventing
potential substrates from accessing its active site. As a result,
it is secreted from cells as a propeptide-containing,
enzymatically inactive protein. {ECO:0000269|PubMed:16912035}.
-!- PTM: Phosphorylation protects the propeptide against proteolysis.
{ECO:0000269|PubMed:18498363}.
-!- POLYMORPHISM: Variant Leu-23 ins polymorphism in PCSK9 might have
a modifier effect on LDLR mutation and familial
hypercholesterolemia.
-!- POLYMORPHISM: Genetic variations in PCSK9 define the low density
lipoprotein cholesterol level quantitative trait locus 1 (LDLCQ1)
[MIM:603776]. {ECO:0000269|PubMed:19319977,
ECO:0000269|PubMed:22095935, ECO:0000269|PubMed:22417841}.
-!- DISEASE: Hypercholesterolemia, autosomal dominant, 3 (HCHOLA3)
[MIM:603776]: A familial condition characterized by elevated
circulating cholesterol contained in either low-density
lipoproteins alone or also in very-low-density lipoproteins.
{ECO:0000269|PubMed:12730697, ECO:0000269|PubMed:18799458,
ECO:0000269|PubMed:24808179}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-!- SIMILARITY: Belongs to the peptidase S8 family. {ECO:0000305}.
-!- SEQUENCE CAUTION:
Sequence=BAC11572.1; Type=Frameshift; Positions=494; Evidence={ECO:0000305};
-!- WEB RESOURCE: Name=SeattleSNPs;
URL="http://pga.gs.washington.edu/data/pcsk9/";
-----------------------------------------------------------------------
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EMBL; AX127530; CAC38896.1; -; mRNA.
EMBL; EF692496; ABV59216.1; -; mRNA.
EMBL; AK075365; BAC11572.1; ALT_FRAME; mRNA.
EMBL; AK124635; BAC85910.1; -; mRNA.
EMBL; AY829011; AAV67948.1; -; Genomic_DNA.
EMBL; FJ525880; ACN81318.1; -; Genomic_DNA.
EMBL; AL589790; CAI17845.1; -; Genomic_DNA.
EMBL; AC091609; CAI17845.1; JOINED; Genomic_DNA.
EMBL; CH471059; EAX06660.1; -; Genomic_DNA.
CCDS; CCDS603.1; -. [Q8NBP7-1]
RefSeq; NP_777596.2; NM_174936.3. [Q8NBP7-1]
UniGene; Hs.18844; -.
PDB; 2P4E; X-ray; 1.98 A; A/P=1-692.
PDB; 2PMW; X-ray; 2.30 A; A=31-152, B=153-692.
PDB; 2QTW; X-ray; 1.90 A; A=29-152, B=153-692.
PDB; 2W2M; X-ray; 2.40 A; A=153-451, P=53-152.
PDB; 2W2N; X-ray; 2.30 A; A=153-451, P=53-152.
PDB; 2W2O; X-ray; 2.62 A; A=153-451, P=53-152.
PDB; 2W2P; X-ray; 2.62 A; A=153-451, P=53-152.
PDB; 2W2Q; X-ray; 2.33 A; A=153-451, P=53-152.
PDB; 2XTJ; X-ray; 2.70 A; A=153-451, P=53-152.
PDB; 3BPS; X-ray; 2.41 A; A=153-692, P=53-152.
PDB; 3GCW; X-ray; 2.70 A; A=153-692, P=53-152.
PDB; 3GCX; X-ray; 2.70 A; A=153-692, P=53-152.
PDB; 3H42; X-ray; 2.30 A; A=31-152, B=153-692.
PDB; 3M0C; X-ray; 7.01 A; A=29-152, B=153-692.
PDB; 3P5B; X-ray; 3.30 A; A=153-692, P=61-152.
PDB; 3P5C; X-ray; 4.20 A; A=153-692, P=61-152.
PDB; 3SQO; X-ray; 2.70 A; A=153-692, P=31-152.
PDB; 4K8R; X-ray; 3.22 A; A=61-152, B=153-692.
PDB; 4NE9; X-ray; 2.60 A; A/B=153-692, C/P=1-152.
PDB; 4NMX; X-ray; 1.85 A; A=31-152, B=153-452.
PDB; 4OV6; X-ray; 2.69 A; A/D=60-152, B/E=153-446.
PDB; 5VLA; X-ray; 2.40 A; A=1-452.
PDB; 5VLH; X-ray; 2.86 A; A=1-452.
PDB; 5VLK; X-ray; 2.20 A; A=1-452.
PDB; 5VLL; X-ray; 2.37 A; A=1-452.
PDB; 5VLP; X-ray; 2.90 A; A=1-692.
PDBsum; 2P4E; -.
PDBsum; 2PMW; -.
PDBsum; 2QTW; -.
PDBsum; 2W2M; -.
PDBsum; 2W2N; -.
PDBsum; 2W2O; -.
PDBsum; 2W2P; -.
PDBsum; 2W2Q; -.
PDBsum; 2XTJ; -.
PDBsum; 3BPS; -.
PDBsum; 3GCW; -.
PDBsum; 3GCX; -.
PDBsum; 3H42; -.
PDBsum; 3M0C; -.
PDBsum; 3P5B; -.
PDBsum; 3P5C; -.
PDBsum; 3SQO; -.
PDBsum; 4K8R; -.
PDBsum; 4NE9; -.
PDBsum; 4NMX; -.
PDBsum; 4OV6; -.
PDBsum; 5VLA; -.
PDBsum; 5VLH; -.
PDBsum; 5VLK; -.
PDBsum; 5VLL; -.
PDBsum; 5VLP; -.
ProteinModelPortal; Q8NBP7; -.
SMR; Q8NBP7; -.
BioGrid; 129116; 26.
DIP; DIP-29694N; -.
IntAct; Q8NBP7; 5.
MINT; MINT-3041747; -.
STRING; 9606.ENSP00000303208; -.
BindingDB; Q8NBP7; -.
ChEMBL; CHEMBL2929; -.
DrugBank; DB09302; Alirocumab.
DrugBank; DB09303; Evolocumab.
GuidetoPHARMACOLOGY; 2388; -.
MEROPS; S08.039; -.
iPTMnet; Q8NBP7; -.
PhosphoSitePlus; Q8NBP7; -.
BioMuta; PCSK9; -.
DMDM; 317373487; -.
EPD; Q8NBP7; -.
MaxQB; Q8NBP7; -.
PaxDb; Q8NBP7; -.
PeptideAtlas; Q8NBP7; -.
PRIDE; Q8NBP7; -.
DNASU; 255738; -.
Ensembl; ENST00000302118; ENSP00000303208; ENSG00000169174. [Q8NBP7-1]
GeneID; 255738; -.
KEGG; hsa:255738; -.
UCSC; uc001cyf.3; human. [Q8NBP7-1]
CTD; 255738; -.
DisGeNET; 255738; -.
EuPathDB; HostDB:ENSG00000169174.10; -.
GeneCards; PCSK9; -.
GeneReviews; PCSK9; -.
H-InvDB; HIX0023558; -.
HGNC; HGNC:20001; PCSK9.
MalaCards; PCSK9; -.
MIM; 603776; phenotype.
MIM; 607786; gene.
neXtProt; NX_Q8NBP7; -.
OpenTargets; ENSG00000169174; -.
Orphanet; 426; Familial hypobetalipoproteinemia.
Orphanet; 406; Heterozygous familial hypercholesterolemia.
Orphanet; 391665; Homozygous familial hypercholesterolemia.
PharmGKB; PA38617; -.
eggNOG; KOG1153; Eukaryota.
eggNOG; COG1404; LUCA.
GeneTree; ENSGT00490000043472; -.
HOGENOM; HOG000049267; -.
HOVERGEN; HBG053530; -.
InParanoid; Q8NBP7; -.
KO; K13050; -.
OMA; HVLTGCS; -.
OrthoDB; EOG091G067E; -.
PhylomeDB; Q8NBP7; -.
TreeFam; TF106271; -.
BRENDA; 3.4.21.61; 2681.
Reactome; R-HSA-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
Reactome; R-HSA-8866427; VLDLR internalisation and degradation.
Reactome; R-HSA-8957275; Post-translational protein phosphorylation.
Reactome; R-HSA-8964038; LDL clearance.
SignaLink; Q8NBP7; -.
SIGNOR; Q8NBP7; -.
EvolutionaryTrace; Q8NBP7; -.
GeneWiki; PCSK9; -.
GenomeRNAi; 255738; -.
PRO; PR:Q8NBP7; -.
Proteomes; UP000005640; Chromosome 1.
Bgee; ENSG00000169174; -.
CleanEx; HS_PCSK9; -.
Genevisible; Q8NBP7; HS.
GO; GO:0009986; C:cell surface; IDA:UniProtKB.
GO; GO:0030134; C:COPII-coated ER to Golgi transport vesicle; IEA:Ensembl.
GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
GO; GO:0005769; C:early endosome; IDA:UniProtKB.
GO; GO:0036020; C:endolysosome membrane; TAS:Reactome.
GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
GO; GO:0005576; C:extracellular region; TAS:Reactome.
GO; GO:0005615; C:extracellular space; IDA:HGNC.
GO; GO:0031232; C:extrinsic component of external side of plasma membrane; IC:BHF-UCL.
GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
GO; GO:0005770; C:late endosome; IDA:UniProtKB.
GO; GO:0005765; C:lysosomal membrane; TAS:Reactome.
GO; GO:0005764; C:lysosome; IDA:UniProtKB.
GO; GO:1990667; C:PCSK9-AnxA2 complex; IDA:BHF-UCL.
GO; GO:1990666; C:PCSK9-LDLR complex; IDA:BHF-UCL.
GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:BHF-UCL.
GO; GO:0005886; C:plasma membrane; IDA:BHF-UCL.
GO; GO:0005791; C:rough endoplasmic reticulum; IEA:Ensembl.
GO; GO:0034185; F:apolipoprotein binding; ISS:UniProtKB.
GO; GO:0034190; F:apolipoprotein receptor binding; IDA:BHF-UCL.
GO; GO:0030169; F:low-density lipoprotein particle binding; ISS:UniProtKB.
GO; GO:0050750; F:low-density lipoprotein particle receptor binding; IDA:HGNC.
GO; GO:0043621; F:protein self-association; IDA:UniProtKB.
GO; GO:0030547; F:receptor inhibitor activity; IDA:BHF-UCL.
GO; GO:0003723; F:RNA binding; IDA:UniProtKB.
GO; GO:0004252; F:serine-type endopeptidase activity; IDA:HGNC.
GO; GO:0019871; F:sodium channel inhibitor activity; IDA:UniProtKB.
GO; GO:0034189; F:very-low-density lipoprotein particle binding; ISS:UniProtKB.
GO; GO:0070326; F:very-low-density lipoprotein particle receptor binding; IDA:BHF-UCL.
GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
GO; GO:0044267; P:cellular protein metabolic process; TAS:Reactome.
GO; GO:0032869; P:cellular response to insulin stimulus; ISS:HGNC.
GO; GO:0009267; P:cellular response to starvation; ISS:HGNC.
GO; GO:0042632; P:cholesterol homeostasis; IMP:HGNC.
GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW.
GO; GO:0001822; P:kidney development; ISS:HGNC.
GO; GO:0042157; P:lipoprotein metabolic process; IEA:Ensembl.
GO; GO:0001889; P:liver development; ISS:HGNC.
GO; GO:0034383; P:low-density lipoprotein particle clearance; TAS:Reactome.
GO; GO:0032802; P:low-density lipoprotein particle receptor catabolic process; IDA:UniProtKB.
GO; GO:0007041; P:lysosomal transport; IDA:BHF-UCL.
GO; GO:0010989; P:negative regulation of low-density lipoprotein particle clearance; IDA:BHF-UCL.
GO; GO:1905596; P:negative regulation of low-density lipoprotein particle receptor binding; IDA:BHF-UCL.
GO; GO:1905598; P:negative regulation of low-density lipoprotein receptor activity; IDA:BHF-UCL.
GO; GO:0001920; P:negative regulation of receptor recycling; IDA:BHF-UCL.
GO; GO:1905601; P:negative regulation of receptor-mediated endocytosis involved in cholesterol transport; IDA:BHF-UCL.
GO; GO:2000650; P:negative regulation of sodium ion transmembrane transporter activity; IDA:BHF-UCL.
GO; GO:0022008; P:neurogenesis; ISS:HGNC.
GO; GO:0030182; P:neuron differentiation; ISS:HGNC.
GO; GO:0006644; P:phospholipid metabolic process; IEA:Ensembl.
GO; GO:0032805; P:positive regulation of low-density lipoprotein particle receptor catabolic process; IDA:BHF-UCL.
GO; GO:0043525; P:positive regulation of neuron apoptotic process; IMP:HGNC.
GO; GO:0002092; P:positive regulation of receptor internalization; IDA:BHF-UCL.
GO; GO:0043687; P:post-translational protein modification; TAS:Reactome.
GO; GO:0016540; P:protein autoprocessing; IDA:HGNC.
GO; GO:0043523; P:regulation of neuron apoptotic process; ISS:UniProtKB.
GO; GO:0010469; P:regulation of receptor activity; IDA:BHF-UCL.
GO; GO:0006641; P:triglyceride metabolic process; IEA:Ensembl.
CDD; cd04077; Peptidases_S8_PCSK9_Proteinase; 1.
Gene3D; 3.30.70.80; -; 1.
Gene3D; 3.40.50.200; -; 1.
InterPro; IPR034193; PCSK9_ProteinaseK-like.
InterPro; IPR009020; Peptidase/Inhibitor_I9.
InterPro; IPR000209; Peptidase_S8/S53_dom.
InterPro; IPR036852; Peptidase_S8/S53_dom_sf.
InterPro; IPR015500; Peptidase_S8_subtilisin-rel.
InterPro; IPR010259; S8pro/Inhibitor_I9.
InterPro; IPR037045; S8pro/Inhibitor_I9_sf.
Pfam; PF05922; Inhibitor_I9; 1.
Pfam; PF00082; Peptidase_S8; 1.
PRINTS; PR00723; SUBTILISIN.
SUPFAM; SSF52743; SSF52743; 1.
SUPFAM; SSF54897; SSF54897; 1.
1: Evidence at protein level;
3D-structure; Alternative splicing; Apoptosis; Autocatalytic cleavage;
Calcium; Cholesterol metabolism; Complete proteome; Cytoplasm;
Direct protein sequencing; Disease mutation; Disulfide bond;
Endoplasmic reticulum; Endosome; Glycoprotein; Golgi apparatus;
Hydrolase; Lipid metabolism; Lysosome; Phosphoprotein; Polymorphism;
Protease; Reference proteome; Secreted; Serine protease; Signal;
Steroid metabolism; Sterol metabolism; Sulfation; Zymogen.
SIGNAL 1 30 {ECO:0000269|PubMed:12552133}.
PROPEP 31 152 {ECO:0000269|PubMed:12552133}.
/FTId=PRO_0000027120.
CHAIN 153 692 Proprotein convertase subtilisin/kexin
type 9.
/FTId=PRO_0000027121.
DOMAIN 182 424 Peptidase S8.
REGION 450 692 C-terminal domain.
ACT_SITE 186 186 Charge relay system. {ECO:0000250}.
ACT_SITE 226 226 Charge relay system. {ECO:0000250}.
ACT_SITE 386 386 Charge relay system. {ECO:0000250}.
SITE 152 153 Cleavage; by autolysis.
SITE 218 219 Cleavage; by furin and PCSK5.
MOD_RES 38 38 Sulfotyrosine.
{ECO:0000269|PubMed:16912035}.
MOD_RES 47 47 Phosphoserine; by FAM20C.
{ECO:0000269|PubMed:18498363,
ECO:0000269|PubMed:26091039}.
MOD_RES 688 688 Phosphoserine; by FAM20C.
{ECO:0000244|PubMed:17081983,
ECO:0000244|PubMed:20068231,
ECO:0000244|PubMed:21406692,
ECO:0000244|PubMed:23186163,
ECO:0000269|PubMed:18498363,
ECO:0000269|PubMed:26091039}.
CARBOHYD 533 533 N-linked (GlcNAc...) asparagine.
{ECO:0000269|PubMed:16912035}.
DISULFID 223 255 {ECO:0000255}.
DISULFID 323 358 {ECO:0000255}.
DISULFID 457 527 {ECO:0000255}.
DISULFID 477 526 {ECO:0000255}.
DISULFID 486 509 {ECO:0000255}.
DISULFID 534 601 {ECO:0000255}.
DISULFID 552 600 {ECO:0000255}.
DISULFID 562 588 {ECO:0000255}.
DISULFID 608 679 {ECO:0000255}.
DISULFID 626 678 {ECO:0000255}.
DISULFID 635 654 {ECO:0000255}.
VAR_SEQ 1 174 MGTVSSRRSWWPLPLLLLLLLLLGPAGARAQEDEDGDYEEL
VLALRSEEDGLAEAPEHGTTATFHRCAKDPWRLPGTYVVVL
KEETHLSQSERTARRLQAQAARRGYLTKILHVFHGLLPGFL
VKMSGDLLELALKLPHVDYIEEDSSVFAQSIPWNLERITPP
RYRADEYQPP -> MSPWK (in isoform 2).
{ECO:0000303|PubMed:14702039}.
/FTId=VSP_008844.
VAR_SEQ 333 365 VITVGATNAQDQPVTLGTLGTNFGRCVDLFAPG -> GRTS
LVPPATAAPALCHRVGHHRLLPTWLALQP (in isoform
2). {ECO:0000303|PubMed:14702039}.
/FTId=VSP_008845.
VAR_SEQ 366 692 Missing (in isoform 2).
{ECO:0000303|PubMed:14702039}.
/FTId=VSP_008846.
VARIANT 23 23 L -> LL (this polymoprhism seems to have
a modifier effect on LDLR mutation and
familial hypercholesterolemia).
{ECO:0000269|PubMed:19319977,
ECO:0000269|PubMed:22095935,
ECO:0000269|Ref.4, ECO:0000269|Ref.5}.
/FTId=VAR_021336.
VARIANT 46 46 R -> L (polymorphism; associated with
lower plasma levels of low-density
lipoprotein cholesterol; reduced
phosphorylation at Ser-47;
dbSNP:rs11591147).
{ECO:0000269|PubMed:12730697,
ECO:0000269|PubMed:16465619,
ECO:0000269|PubMed:22095935,
ECO:0000269|Ref.4}.
/FTId=VAR_017197.
VARIANT 53 53 A -> V (polymorphism; associated with
reduced phosphorylation at Ser-47;
dbSNP:rs11583680).
{ECO:0000269|PubMed:12730697,
ECO:0000269|PubMed:16465619,
ECO:0000269|PubMed:22095935,
ECO:0000269|Ref.4}.
/FTId=VAR_017198.
VARIANT 57 57 E -> K (in dbSNP:rs145886902).
{ECO:0000269|PubMed:16465619}.
/FTId=VAR_025451.
VARIANT 77 77 T -> I (in dbSNP:rs756060557).
/FTId=VAR_058520.
VARIANT 93 93 R -> C (in dbSNP:rs151193009).
/FTId=VAR_058521.
VARIANT 106 106 G -> R.
/FTId=VAR_058522.
VARIANT 114 114 V -> A (in dbSNP:rs775988212).
/FTId=VAR_058523.
VARIANT 127 127 S -> R (in HCHOLA3; dbSNP:rs28942111).
{ECO:0000269|PubMed:12730697}.
/FTId=VAR_017199.
VARIANT 129 129 D -> G (in HCHOLA3).
/FTId=VAR_058524.
VARIANT 157 157 N -> K (in dbSNP:rs143117125).
/FTId=VAR_058525.
VARIANT 174 174 P -> S (found in patients with familial
hypercholesterolemia carrying a
homozygous LDLR mutation; acts as a
disease modifier resulting in a mild
phenotype; dbSNP:rs533273863).
{ECO:0000269|PubMed:22417841}.
/FTId=VAR_067351.
VARIANT 215 215 R -> H (in HCHOLA3; dbSNP:rs794728683).
/FTId=VAR_058526.
VARIANT 216 216 F -> L (in HCHOLA3; partial loss of
cleavage by furin and PCSK5;
dbSNP:rs28942112).
{ECO:0000269|PubMed:12730697}.
/FTId=VAR_017200.
VARIANT 218 218 R -> S (in HCHOLA3; complete loss of
cleavage by furin and PCSK5; reduces
glycosylation levels; no effect on
protein sulfation and phosphorylation; no
effect on protein sulfation but inhibits
phosphorylation when associated with Y-
374; highly reduces LDL uptake when
associated with Y-374).
{ECO:0000269|PubMed:18799458,
ECO:0000269|PubMed:24808179}.
/FTId=VAR_058527.
VARIANT 219 219 Q -> E (in dbSNP:rs778617372).
/FTId=VAR_058528.
VARIANT 237 237 R -> W (in dbSNP:rs148195424).
{ECO:0000269|PubMed:16465619}.
/FTId=VAR_025452.
VARIANT 239 239 A -> D.
/FTId=VAR_058529.
VARIANT 253 253 L -> F (polymorphism; associated with
lower plasma levels of low-density
lipoprotein cholesterol;
dbSNP:rs28362270).
{ECO:0000269|PubMed:16465619}.
/FTId=VAR_025453.
VARIANT 357 357 R -> H (in HCHOLA3; dbSNP:rs370507566).
/FTId=VAR_058530.
VARIANT 374 374 D -> H (in HCHOLA3).
/FTId=VAR_058531.
VARIANT 374 374 D -> Y (in HCHOLA3; partial loss of
cleavage by furin and PCSK5; no effect on
protein sulfation but inhibits
phosphorylation when associated with S-
218; highly increases LDL uptake when
associated with S-218;
dbSNP:rs137852912).
{ECO:0000269|PubMed:18799458,
ECO:0000269|PubMed:24808179}.
/FTId=VAR_058532.
VARIANT 391 391 H -> N (in dbSNP:rs146471967).
{ECO:0000269|PubMed:16465619}.
/FTId=VAR_025454.
VARIANT 394 394 G -> S (found in a patient associated
with autosomal dominant
hypercholesterolemia; unknown
pathological significance;
dbSNP:rs368257906).
{ECO:0000269|PubMed:22095935}.
/FTId=VAR_067282.
VARIANT 417 417 H -> Q (in dbSNP:rs143275858).
{ECO:0000269|PubMed:16465619}.
/FTId=VAR_025455.
VARIANT 425 425 N -> S (in dbSNP:rs28362261).
{ECO:0000269|PubMed:16465619,
ECO:0000269|Ref.4}.
/FTId=VAR_021337.
VARIANT 443 443 A -> T (polymorphism; associated with
lower plasma levels of low-density
lipoprotein cholesterol; more extensive
cleavage by furin and PCSK5;
dbSNP:rs28362263).
{ECO:0000269|PubMed:16465619,
ECO:0000269|Ref.4}.
/FTId=VAR_021338.
VARIANT 452 452 G -> D.
/FTId=VAR_058533.
VARIANT 469 469 R -> W (in dbSNP:rs141502002).
{ECO:0000269|PubMed:16465619}.
/FTId=VAR_025456.
VARIANT 474 474 V -> I (in dbSNP:rs562556).
{ECO:0000269|PubMed:14702039,
ECO:0000269|PubMed:16465619,
ECO:0000269|PubMed:17971861,
ECO:0000269|PubMed:22095935,
ECO:0000269|Ref.1, ECO:0000269|Ref.4,
ECO:0000269|Ref.5, ECO:0000269|Ref.7}.
/FTId=VAR_021339.
VARIANT 482 482 E -> G (in dbSNP:rs141995194).
{ECO:0000269|PubMed:16465619}.
/FTId=VAR_025457.
VARIANT 482 482 E -> Q (no effect on interaction with
ANXA2). {ECO:0000269|PubMed:24808179}.
/FTId=VAR_073657.
VARIANT 496 496 R -> W (in HCHOLA3; dbSNP:rs374603772).
/FTId=VAR_058534.
VARIANT 515 515 F -> L. {ECO:0000269|PubMed:16465619}.
/FTId=VAR_025458.
VARIANT 522 522 A -> T (in dbSNP:rs777300852).
/FTId=VAR_058535.
VARIANT 553 553 H -> R (in dbSNP:rs28362270).
{ECO:0000269|PubMed:16465619,
ECO:0000269|Ref.4}.
/FTId=VAR_021340.
VARIANT 554 554 Q -> E (increases interaction with ANXA2;
dbSNP:rs149311926).
{ECO:0000269|PubMed:16465619,
ECO:0000269|PubMed:18799458}.
/FTId=VAR_025459.
VARIANT 616 616 P -> L (in dbSNP:rs755750316).
/FTId=VAR_058536.
VARIANT 619 619 Q -> P (in dbSNP:rs28362277).
{ECO:0000269|PubMed:16465619,
ECO:0000269|Ref.4}.
/FTId=VAR_021341.
VARIANT 668 668 S -> R (in dbSNP:rs762298323).
/FTId=VAR_058537.
VARIANT 670 670 G -> E (in dbSNP:rs505151).
{ECO:0000269|PubMed:12730697,
ECO:0000269|PubMed:16465619,
ECO:0000269|PubMed:17971861,
ECO:0000269|PubMed:22095935,
ECO:0000269|Ref.1, ECO:0000269|Ref.4,
ECO:0000269|Ref.5, ECO:0000269|Ref.7}.
/FTId=VAR_017201.
MUTAGEN 67 67 C->A: Does not affect multimerization or
zymogen processing.
{ECO:0000269|PubMed:12552133}.
MUTAGEN 226 226 H->A: Remains in the endoplasmic
reticulum and is not secreted.
{ECO:0000269|PubMed:12552133}.
MUTAGEN 533 533 N->A: 1.5 kDa decrease of the apparent
molecular mass of pro-PCSK9 and PCSK9 and
no effect on processing and secretion.
{ECO:0000269|PubMed:12552133}.
CONFLICT 423 423 V -> A (in Ref. 3; BAC11572).
{ECO:0000305}.
STRAND 63 65 {ECO:0000244|PDB:4NMX}.
HELIX 70 72 {ECO:0000244|PDB:4NMX}.
STRAND 73 82 {ECO:0000244|PDB:4NMX}.
STRAND 84 86 {ECO:0000244|PDB:4OV6}.
HELIX 88 104 {ECO:0000244|PDB:4NMX}.
STRAND 110 115 {ECO:0000244|PDB:4NMX}.
STRAND 117 119 {ECO:0000244|PDB:4NMX}.
STRAND 121 125 {ECO:0000244|PDB:4NMX}.
HELIX 128 130 {ECO:0000244|PDB:4NMX}.
HELIX 131 135 {ECO:0000244|PDB:4NMX}.
STRAND 140 151 {ECO:0000244|PDB:4NMX}.
HELIX 156 160 {ECO:0000244|PDB:4NMX}.
HELIX 168 170 {ECO:0000244|PDB:3BPS}.
STRAND 181 187 {ECO:0000244|PDB:4NMX}.
TURN 194 199 {ECO:0000244|PDB:4NMX}.
STRAND 200 206 {ECO:0000244|PDB:4NMX}.
STRAND 212 214 {ECO:0000244|PDB:4NMX}.
TURN 218 220 {ECO:0000244|PDB:3H42}.
TURN 221 224 {ECO:0000244|PDB:2QTW}.
HELIX 225 235 {ECO:0000244|PDB:4NMX}.
TURN 237 239 {ECO:0000244|PDB:4NMX}.
STRAND 241 244 {ECO:0000244|PDB:2P4E}.
STRAND 246 251 {ECO:0000244|PDB:4NMX}.
STRAND 257 260 {ECO:0000244|PDB:4NMX}.
HELIX 261 277 {ECO:0000244|PDB:4NMX}.
STRAND 283 287 {ECO:0000244|PDB:4NMX}.
STRAND 289 292 {ECO:0000244|PDB:4NMX}.
HELIX 295 306 {ECO:0000244|PDB:4NMX}.
STRAND 310 314 {ECO:0000244|PDB:4NMX}.
STRAND 317 321 {ECO:0000244|PDB:4NMX}.
HELIX 322 324 {ECO:0000244|PDB:4NMX}.
TURN 327 329 {ECO:0000244|PDB:4NMX}.
STRAND 333 339 {ECO:0000244|PDB:4NMX}.
STRAND 343 345 {ECO:0000244|PDB:2PMW}.
STRAND 349 352 {ECO:0000244|PDB:2W2Q}.
STRAND 355 358 {ECO:0000244|PDB:3P5B}.
STRAND 361 364 {ECO:0000244|PDB:4NMX}.
STRAND 366 372 {ECO:0000244|PDB:4NMX}.
STRAND 373 375 {ECO:0000244|PDB:5VLL}.
STRAND 378 382 {ECO:0000244|PDB:4NMX}.
HELIX 385 402 {ECO:0000244|PDB:4NMX}.
HELIX 408 417 {ECO:0000244|PDB:4NMX}.
STRAND 419 422 {ECO:0000244|PDB:4NMX}.
HELIX 426 428 {ECO:0000244|PDB:4NMX}.
HELIX 431 433 {ECO:0000244|PDB:4NMX}.
TURN 434 436 {ECO:0000244|PDB:4NMX}.
STRAND 440 442 {ECO:0000244|PDB:3P5B}.
STRAND 456 461 {ECO:0000244|PDB:2QTW}.
STRAND 467 470 {ECO:0000244|PDB:3SQO}.
STRAND 472 475 {ECO:0000244|PDB:2QTW}.
STRAND 482 489 {ECO:0000244|PDB:2QTW}.
STRAND 491 493 {ECO:0000244|PDB:3GCX}.
STRAND 495 503 {ECO:0000244|PDB:2QTW}.
STRAND 506 513 {ECO:0000244|PDB:2QTW}.
STRAND 521 528 {ECO:0000244|PDB:2QTW}.
STRAND 533 539 {ECO:0000244|PDB:2QTW}.
STRAND 544 546 {ECO:0000244|PDB:2QTW}.
STRAND 548 551 {ECO:0000244|PDB:2QTW}.
STRAND 558 565 {ECO:0000244|PDB:2QTW}.
STRAND 568 570 {ECO:0000244|PDB:2P4E}.
STRAND 587 590 {ECO:0000244|PDB:2QTW}.
STRAND 594 602 {ECO:0000244|PDB:2QTW}.
STRAND 606 615 {ECO:0000244|PDB:2QTW}.
STRAND 621 625 {ECO:0000244|PDB:2QTW}.
STRAND 631 637 {ECO:0000244|PDB:2QTW}.
STRAND 644 650 {ECO:0000244|PDB:2QTW}.
STRAND 653 658 {ECO:0000244|PDB:2QTW}.
STRAND 672 681 {ECO:0000244|PDB:2QTW}.
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


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