PCSK9

Proprotein convertase subtilisin/kexin type 9
PDB rendering based on 2p4e.
Available structures PDB 2P4E, 2PMW, 2QTW, 2W2M, 2W2N, 2W2O, 2W2P, 2W2Q, 2XTJ, 3BPS, 3GCW, 3GCX, 3H42
Identifiers
Symbols	PCSK9; FH3; HCHOLA3; LDLCQ1; NARC-1; NARC1; PC9
External IDs	OMIM: 607786 MGI: 2140260 HomoloGene: 17790 GeneCards: PCSK9 Gene
EC number	3.4.21.-
Gene Ontology Molecular function • serine-type endopeptidase activity • peptidase activity • apolipoprotein receptor binding • identical protein binding • low-density lipoprotein particle receptor binding • low-density lipoprotein particle receptor binding • very-low-density lipoprotein particle receptor binding Cellular component • extracellular region • extracellular space • lysosome • late endosome • rough endoplasmic reticulum • extrinsic to external side of plasma membrane • perinuclear region of cytoplasm Biological process • kidney development • liver development • negative regulation of receptor recycling • positive regulation of receptor internalization • proteolysis • triglyceride metabolic process • phospholipid metabolic process • induction of apoptosis • lysosomal transport • steroid metabolic process • cholesterol metabolic process • cellular response to starvation • regulation of receptor activity • negative regulation of low-density lipoprotein particle clearance • protein autoprocessing • neurogenesis • neuron differentiation • low-density lipoprotein particle receptor catabolic process • regulation of low-density lipoprotein particle receptor catabolic process • cellular response to insulin stimulus • lipoprotein metabolic process • cholesterol homeostasis • negative regulation of catalytic activity • positive regulation of neuron apoptosis • protein maturation by peptide bond cleavage Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	255738	100102
Ensembl	ENSG00000169174	ENSMUSG00000044254
UniProt	Q8NBP7	Q5PYH4
RefSeq (mRNA)	NM_174936.3	NM_153565.2
RefSeq (protein)	NP_777596.2	NP_705793.1
Location (UCSC)	Chr 1: 55.51 – 55.53 Mb	Chr 4: 106.11 – 106.14 Mb
PubMed search	[1]	[2]

Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is an enzyme which in humans is encoded by the PCSK9 gene^[1] with orthologs found across many species.

Function

This gene encodes a proprotein convertase belonging to the proteinase K subfamily of the secretory subtilase family. The encoded protein is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum. The protein may function as a proprotein convertase.

This protein plays a major regulatory role in cholesterol homeostasis. PCSK9 binds to the epidermal growth factor-like repeat A (EGF-A) domain of the low-density lipoprotein receptor (LDLR), inducing LDLR degradation. Reduced LDLR levels result in decreased metabolism of low-density lipoproteins, which could lead to hypercholesterolemia.

PCSK9 may also have a role in the differentiation of cortical neurons.^[1]

Clinical significance

Mutations in this gene have been associated with a rare form of autosomal dominant familial hypercholesterolemia (HCHOLA3).^[2][3][4]

The mutations appear to cause the disease by increasing its protease activity, reducing LDL receptor levels and thereby preventing the uptake of cholesterol into the cells.^[3]

Several variants of PCSK9 have also been shown to significantly reduce circulating cholesterol. Some variants, which only reduce cholesterol by 15% in whites, has been shown to produce a concurrent reduction in coronary heart disease by 50%, which has major implications for public health.

Inhibition of PCSK9 function is currently being explored as a means of lowering cholesterol levels.^[5][6][7][8]

References

1. ^ ^{a b} Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M (February 2003). "The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiation". Proc. Natl. Acad. Sci. U.S.A. 100 (3): 928–33. doi:10.1073/pnas.0335507100. PMC 298703. PMID 12552133. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=298703. 
2. ^ "Entrez Gene: PCSK9 proprotein convertase subtilisin/kexin type 9". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=255738. 
3. ^ ^{a b} Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C (June 2003). "Mutations in PCSK9 cause autosomal dominant hypercholesterolemia". Nat. Genet. 34 (2): 154–6. doi:10.1038/ng1161. PMID 12730697. 
4. ^ Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L, Prat A (August 2004). "Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia". Arterioscler. Thromb. Vasc. Biol. 24 (8): 1454–9. doi:10.1161/01.ATV.0000134621.14315.43. PMID 15178557. 
5. ^ Lopez D (2008). "Inhibition of PCSK9 as a novel strategy for the treatment of hypercholesterolemia". Drug News Perspect. 21 (6): 323–30. doi:10.1358/dnp.2008.21.6.1246795. PMID 18836590. 
6. ^ Steinberg D, Witztum JL (June 2009). "Inhibition of PCSK9: A powerful weapon for achieving ideal LDL cholesterol levels". Proc. Natl. Acad. Sci. U.S.A. 106 (24): 9546–7. doi:10.1073/pnas.0904560106. PMC 2701045. PMID 19506257. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2701045. 
7. ^ Mayer G, Poirier S, Seidah NG (November 2008). "Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels". J. Biol. Chem. 283 (46): 31791–801. doi:10.1074/jbc.M805971200. PMID 18799458. 
8. ^ "Bristol-Myers Squibb selects Isis drug targeting PCSK9 as development candidate for prevention and treatment of cardiovascular disease". Press Release. FierceBiotech. 2008-04-08. http://www.fiercebiotech.com/press-releases/bristol-myers-squibb-selects-isis-drug-targeting-pcsk9-development-candidate-preventi. Retrieved 2010-09-18. 

Further reading

• Abifadel M, Rabès JP, Boileau C, Varret M (2007). "[After the LDL receptor and apolipoprotein B, autosomal dominant hypercholesterolemia reveals its third protagonist: PCSK9]". Ann. Endocrinol. (Paris) 68 (2–3): 138–46. doi:10.1016/j.ando.2007.02.002. PMID 17391637. 
• Lambert G (2007). "Unravelling the functional significance of PCSK9". Curr. Opin. Lipidol. 18 (3): 304–9. doi:10.1097/MOL.0b013e3281338531. PMID 17495605. 
• Varret M, Rabès JP, Saint-Jore B, et al. (1999). "A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32". Am. J. Hum. Genet. 64 (5): 1378–87. doi:10.1086/302370. PMC 1377874. PMID 10205269. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1377874. 
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241. 
• Seidah NG, Benjannet S, Wickham L, et al. (2003). "The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiation". Proc. Natl. Acad. Sci. U.S.A. 100 (3): 928–33. doi:10.1073/pnas.0335507100. PMC 298703. PMID 12552133. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=298703. 
• Naureckiene S, Ma L, Sreekumar K, et al. (2004). "Functional characterization of Narc 1, a novel proteinase related to proteinase K". Arch. Biochem. Biophys. 420 (1): 55–67. doi:10.1016/j.abb.2003.09.011. PMID 14622975. 
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039. 
• Timms KM, Wagner S, Samuels ME, et al. (2004). "A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree". Hum. Genet. 114 (4): 349–53. doi:10.1007/s00439-003-1071-9. PMID 14727179. 
• Leren TP (2004). "Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia". Clin. Genet. 65 (5): 419–22. doi:10.1111/j.0009-9163.2004.0238.x. PMID 15099351. 
• Ouguerram K, Chetiveaux M, Zair Y, et al. (2005). "Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9". Arterioscler. Thromb. Vasc. Biol. 24 (8): 1448–53. doi:10.1161/01.ATV.0000133684.77013.88. PMID 15166014. 
• Benjannet S, Rhainds D, Essalmani R, et al. (2005). "NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol". J. Biol. Chem. 279 (47): 48865–75. doi:10.1074/jbc.M409699200. PMID 15358785. 
• Cohen J, Pertsemlidis A, Kotowski IK, et al. (2005). "Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9". Nat. Genet. 37 (2): 161–5. doi:10.1038/ng1509. PMID 15654334. 
• Lalanne F, Lambert G, Amar MJ, et al. (2005). "Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells". J. Lipid Res. 46 (6): 1312–9. doi:10.1194/jlr.M400396-JLR200. PMID 15741654. 
• Sun XM, Eden ER, Tosi I, et al. (2005). "Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia". Hum. Mol. Genet. 14 (9): 1161–9. doi:10.1093/hmg/ddi128. PMID 15772090. 
• Pisciotta L, Priore Oliva C, Cefalù AB, et al. (2006). "Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia". Atherosclerosis 186 (2): 433–40. doi:10.1016/j.atherosclerosis.2005.08.015. PMID 16183066. 
• Allard D, Amsellem S, Abifadel M, et al. (2006). "Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia". Hum. Mutat. 26 (5): 497. doi:10.1002/humu.9383. PMID 16211558. 
• Naoumova RP, Tosi I, Patel D, et al. (2006). "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response". Arterioscler. Thromb. Vasc. Biol. 25 (12): 2654–60. doi:10.1161/01.ATV.0000190668.94752.ab. PMID 16224054. 
• Shibata N, Ohnuma T, Higashi S, et al. (2006). "No genetic association between PCSK9 polymorphisms and Alzheimer's disease and plasma cholesterol level in Japanese patients". Psychiatr. Genet. 15 (4): 239. doi:10.1097/00041444-200512000-00004. PMID 16314752.