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Protein PCSK9 PDB 2p4e.png
Available structures
PDB Ortholog search: PDBe RCSB
Aliases PCSK9, proprotein convertase subtilisin/kexin type 9, FH3, HCHOLA3, LDLCQ1, NARC-1, NARC1, PC9
External IDs MGI: 2140260 HomoloGene: 17790 GeneCards: 255738
Species Human Mouse
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 1: 55.04 – 55.06 Mb Chr 4: 106.44 – 106.46 Mb
PubMed search [1] [2]
View/Edit Human View/Edit Mouse

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans.[1] PCSK9 binds to the receptor for low-density lipoprotein (LDL) cholesterol.

In the liver, the LDL receptor removes LDL cholesterol from the blood. When PCSK9 binds to the LDL receptor, the receptor is broken down and can no longer remove LDL cholesterol from the blood. If PCSK9 is blocked, more LDL receptors will be present on the surface of the liver and will remove more LDL cholesterol from the blood.[2] Therefore, blocking PCSK9 can lower blood cholesterol levels.[3][4] Similar genes (orthologs) are found across many species. PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme.[5]

PCSK9 has medical significance because it acts in cholesterol homeostasis. Drugs can block PCSK9, thus lowering low-density lipoprotein cholesterol (LDL-C). The first two PCSK9 inhibitors, alirocumab and evolocumab, were approved by the U.S. Food and Drug Administration in 2015 for lowering cholesterol where statins and other drugs were insufficient. The manufacturers did not submit data to show that the drugs actually improved outcomes of cardiovascular disease, but they assumed that lowering cholesterol would treat cardiovascular disease.[6][7]


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.[5]

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 LDL-C, which could lead to hypercholesterolemia.[8] PCSK9 may also have a role in the differentiation of cortical neurons.[1]

Clinical significance[edit]

Variants of PCSK9 can reduce or increase circulating cholesterol. LDL-C is removed from the blood when it binds to an LDLR on the surface of liver cells, and is taken inside the cells. When PCSK9 binds to an LDLR, the receptor is destroyed along with the LDL particle. PCSK9 degrades LDLR by preventing the hairpin conformational change of LDLR.[9] If PCSK9 does not bind, the receptor will return to the surface of the cell and can continue to remove free cholesterol from the bloodstream.[10]

Other variants are associated with a rare autosomal dominant familial hypercholesterolemia (HCHOLA3).[11][12][13] The mutations increase its protease activity, reducing LDLR levels and preventing the uptake of cholesterol into the cells.[12]


In February 2003, Nabil Seidah, a scientist at the Clinical Research Institute of Montreal in Canada, discovered a novel human proprotein convertase, the gene for which was located on the short arm of chromosome 1.[14] Meanwhile, a lab led by Catherine Boileau at the Necker-Enfants Malades Hospital in Paris had been following families with familial hypercholesterolaemia, a genetic condition that, in 90% of cases causes coronary artery disease (FRAMINGHAM study) and in 60% of cases may lead to an early death;[15] they had identified a mutation on chromosome 1 carried by some of these families, but had been unable to identify the relevant gene. The labs got together and by the end of the year published their work, linking mutations in the gene, now identified as PCSK9, to the condition.[14][16] In their paper, they speculated that the mutations might make the gene overactive. In that same year, investigators at Rockefeller University and University of Texas Southwestern had discovered the same protein in mice, and had worked out the novel pathway that regulates LDL cholesterol in which PCSK9 is involved, and it soon became clear that the mutations identified in France led to excessive PCSK9 activity, and thus excessive removal of the LDL receptor, leaving people carrying the mutations with too much LDL cholesterol.[14] Meanwhile, Dr. Helen H. Hobbs and Dr. Jonathan Cohen at UT-Southwestern had been studying people with very high and very low cholesterol, and had been collecting DNA samples. With the new knowledge about the role of PCSK9 and its location in the genome, they sequenced the relevant region of chromosome 1 in people with very low cholesterol and they found nonsense mutations in the gene, thus validating PCSK9 as a biological target for drug discovery.[14][17] In July 2015, the FDA approved the new treatment.[18]

As a drug target[edit]

Drugs can inhibit PCSK9, leading to lowered circulating cholesterol. Since LDL is considered a risk factor for cardiovascular disease like heart attacks, it is plausible that these drugs may also reduce the risk of such diseases. Clinical studies, including phase III clinical trials, are now underway to describe the effect of PCSK9 inhibition on cardiovascular disease, and the safety and efficacy profile of the drugs.[19][20][21][22] Among those inhibitors under development in December 2013 were the antibodies alirocumab, evolocumab, 1D05-IgG2 (Merck), RG-7652 and LY3015014, as well as the RNAi therapeutic ALN-PCS02.[23] PCSK9 inhibitors are promising therapeutics for the treatment of people who exhibit statin intolerance, or as a way to bypass frequent dosage of statins for higher LDL concentration reduction.[24][25]

An FDA warning in March 2014 about possible cognitive adverse effects of PCSK9 inhibition caused concern, as the FDA asked companies to include neurocognitive testing into their Phase III clinical trials.[26]

A review published in 2015 concluded that these agents when used in patients with high cholesterol at risk for cardiovascular disease, seem to be safe and effective at reducing all-cause mortality, cardiovascular mortality, and heart attacks.[27]

Monoclonal antibodies[edit]

A number of monoclonal antibodies that bind to and inhibit PCSK9 near the catalytic domain were in clinical trials as of 2014. These include evolocumab (Amgen), bococizumab (Pfizer), and alirocumab (Aventis/Regeneron).[28] As of July 2015, the EU approved these drugs including Evolocumab/Amgen according to Medscape news agency report. A meta-analysis of 24 clinical trials has shown that monoclonal antibodies against PCSK9 can reduce cholesterol, cardiac events and all-cause mortality.[27]

A possible side effect of the monoclonal antibody might be irritation at the injection site. Before the infusions, participants received oral corticosteroids, histamine receptor blockers, and acetaminophen to reduce the risk of infusion-related reactions, which by themselves will cause several side effects.[29]

Peptide mimics[edit]

Peptides that mimick the EGFA domain of the LDLR that binds to PCSK9 have been developed to inhibit PCSK9.[30]

Gene silencing[edit]

The PCSK9 antisense oligonucleotide increases expression of the LDLR and decreases circulating total cholesterol levels in mice.[31] A locked nucleic acid reduced PCSK9 mRNA levels in mice.[32][33] Initial clinical trials showed positive results of ALN-PCS, which acts by means of RNA interference.[34][35]


A vaccine that targets PCSK9 has been developed to treat high cholesterol. The vaccine uses a VLP (virus-like particle) as an immunogenic carrier of an antigenic PCSK9 peptide. VLP’s are viruses that have had their DNA removed so that they retain their external structure for antigen display but are unable to replicate; they can induce an immune response without causing infection. Mice and macaques vaccinated with bacteriophage VLPs displaying PCSK9-derived peptides developed high-titer IgG antibodies that bound to circulating PCSK9. Vaccination was associated with significant reductions in total cholesterol, free cholesterol, phospholipids, and triglycerides.[36]

Naturally occurring Inhibitors[edit]

The plant alkaloid berberine inhibits the transcription of the PCSK9 gene in immortalized human hepatocytes in vitro;[37] as of yet, there is no evidence that it does so in animals or humans taking berberine supplements.[citation needed] Annexin A2, an endogenous protein, is a natural inhibitor of PCSK9 activity.[38]


2p4e: Crystal structure of PCSK9[39]
2pmw: Crystal structure of proprotein convertase subtilisin kexin type 9 (PCSK9)[40]


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  39. ^ PDB: 2P4ECunningham D, Danley DE, Geoghegan KF, Griffor MC, Hawkins JL, Subashi TA, Varghese AH, Ammirati MJ, Culp JS, Hoth LR, Mansour MN, McGrath KM, Seddon AP, Shenolikar S, Stutzman-Engwall KJ, Warren LC, Xia D, Qiu X (2007). "Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia". Nat. Struct. Mol. Biol. 14 (5): 413–9. doi:10.1038/nsmb1235. PMID 17435765. 
  40. ^ PDB: 2PMWPiper DE, Jackson S, Liu Q, Romanow WG, Shetterly S, Thibault ST, Shan B, Walker NP (2007). "The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol". Structure 15 (5): 545–52. doi:10.1016/j.str.2007.04.004. PMID 17502100. 

Further reading[edit]

  • Abifadel M, Rabès JP, Boileau C, Varret M (June 2007). "[After the LDL receptor and apolipoprotein B, autosomal dominant hypercholesterolemia reveals its third protagonist: PCSK9]". Ann. Endocrinol. (Paris) (in French) 68 (2–3): 138–46. doi:10.1016/j.ando.2007.02.002. PMID 17391637. 
  • Allard D, Amsellem S, Abifadel M, Trillard M, Devillers M, Luc G, Krempf M, Reznik Y, Girardet JP, Fredenrich A, Junien C, Varret M, Boileau C, Benlian P, Rabès JP (November 2005). "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. 
  • Benjannet S, Rhainds D, Essalmani R, Mayne J, Wickham L, Jin W, Asselin MC, Hamelin J, Varret M, Allard D, Trillard M, Abifadel M, Tebon A, Attie AD, Rader DJ, Boileau C, Brissette L, Chrétien M, Prat A, Seidah NG (November 2004). "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, Graham R, Garcia CK, Hobbs HH (February 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, Chétiveaux M, Zaïr Y, Jarnoux AL, Ouguerram K, Friburg J, Seidah NG, Brewer HB, Krempf M, Costet P (June 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. 
  • Lambert G (June 2007). "Unravelling the functional significance of PCSK9". Curr. Opin. Lipidol. 18 (3): 304–9. doi:10.1097/MOL.0b013e3281338531. PMID 17495605. 
  • Leren TP (May 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. 
  • Maxwell KN, Breslow JL (May 2004). "Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype". Proc. Natl. Acad. Sci. U.S.A. 101 (18): 7100–5. doi:10.1073/pnas.0402133101. PMC 406472. PMID 15118091. 
  • Maxwell KN, Soccio RE, Duncan EM, Sehayek E, Breslow JL (November 2003). "Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice". J. Lipid Res. 44 (11): 2109–19. doi:10.1194/jlr.M300203-JLR200. PMID 12897189. 
  • Naoumova RP, Tosi I, Patel D, Neuwirth C, Horswell SD, Marais AD, van Heyningen C, Soutar AK (December 2005). "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. 
  • Naureckiene S, Ma L, Sreekumar K, Purandare U, Lo CF, Huang Y, Chiang LW, Grenier JM, Ozenberger BA, Jacobsen JS, Kennedy JD, DiStefano PS, Wood A, Bingham B (December 2003). "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. 
  • Ouguerram K, Chetiveaux M, Zair Y, Costet P, Abifadel M, Varret M, Boileau C, Magot T, Krempf M (August 2004). "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. 
  • Pisciotta L, Priore Oliva C, Cefalù AB, Noto D, Bellocchio A, Fresa R, Cantafora A, Patel D, Averna M, Tarugi P, Calandra S, Bertolini S (June 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. 
  • Shibata N, Ohnuma T, Higashi S, Higashi M, Usui C, Ohkubo T, Watanabe T, Kawashima R, Kitajima A, Ueki A, Nagao M, Arai H (December 2005). "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. 
  • Sun XM, Eden ER, Tosi I, Neuwirth CK, Wile D, Naoumova RP, Soutar AK (May 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. 
  • Timms KM, Wagner S, Samuels ME, Forbey K, Goldfine H, Jammulapati S, Skolnick MH, Hopkins PN, Hunt SC, Shattuck DM (March 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. 
  • Varret M, Rabès JP, Saint-Jore B, Cenarro A, Marinoni JC, Civeira F, Devillers M, Krempf M, Coulon M, Thiart R, Kotze MJ, Schmidt H, Buzzi JC, Kostner GM, Bertolini S, Pocovi M, Rosa A, Farnier M, Martinez M, Junien C, Boileau C (May 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.