PCSK9

Official Full Name

proprotein convertase subtilisin/kexin type 9

Organism

Homo sapiens

Gene ID

255738

Background

This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an autocatalytic processing event with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestine and kidney tissues and escorts specific receptors for lysosomal degradation. It plays a role in cholesterol and fatty acid metabolism. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

Synonyms

FH3; PC9; FHCL3; NARC1; LDLCQ1; NARC-1; HCHOLA3

Bio Chemical Class

Peptidase

Protein Sequence

MGTVSSRRSWWPLPLLLLLLLLLGPAGARAQEDEDGDYEELVLALRSEEDGLAEAPEHGTTATFHRCAKDPWRLPGTYVVVLKEETHLSQSERTARRLQAQAARRGYLTKILHVFHGLLPGFLVKMSGDLLELALKLPHVDYIEEDSSVFAQSIPWNLERITPPRYRADEYQPPDGGSLVEVYLLDTSIQSDHREIEGRVMVTDFENVPEEDGTRFHRQASKCDSHGTHLAGVVSGRDAGVAKGASMRSLRVLNCQGKGTVSGTLIGLEFIRKSQLVQPVGPLVVLLPLAGGYSRVLNAACQRLARAGVVLVTAAGNFRDDACLYSPASAPEVITVGATNAQDQPVTLGTLGTNFGRCVDLFAPGEDIIGASSDCSTCFVSQSGTSQAAAHVAGIAAMMLSAEPELTLAELRQRLIHFSAKDVINEAWFPEDQRVLTPNLVAALPPSTHGAGWQLFCRTVWSAHSGPTRMATAVARCAPDEELLSCSSFSRSGKRRGERMEAQGGKLVCRAHNAFGGEGVYAIARCCLLPQANCSVHTAPPAEASMGTRVHCHQQGHVLTGCSSHWEVEDLGTHKPPVLRPRGQPNQCVGHREASIHASCCHAPGLECKVKEHGIPAPQEQVTVACEEGWTLTGCSALPGTSHVLGAYAVDNTCVVRSRDVSTTGSTSEGAVTAVAICCRSRHLAQASQELQ

Open

Disease

Cardiovascular disease, Chronic obstructive pulmonary disease, Coronary atherosclerosis, Hyper-lipoproteinaemia, Hyper-lipoproteinaemia

Approved Drug

3 +

Clinical Trial Drug

14 +

Discontinued Drug

Cat.No.	Product Name	Price
CSC-DC011470	Panoply™ Human PCSK9 Knockdown Stable Cell Line	Inquiry
CSC-SC011470	Panoply™ Human PCSK9 Over-expressing Stable Cell Line	Inquiry
CSC-RT0735	Human PCSK9 Knockout Cell Line-HeLa	Inquiry
CLOE-1307	Human PCSK9(His) HEK293 Cell Lysate	Inquiry
CLOE-1310	Human PCSK9 HEK293 Cell Lysate	Inquiry
CLOE-2195	Rat Pcsk9 (His) HEK293 Cell Lysate	Inquiry
CLOE-2807	Mouse Pcsk9 (His) HEK293 Cell Lysate	Inquiry
CLKO-0239	PCSK9 KO Cell Lysate-HeLa	Inquiry

Cat.No.	Product Name	Price
AD11969Z	Human PCSK9 adenoviral particles	Inquiry
LV21261L	human PCSK9 (NM_174936) lentivirus particles	Inquiry

Cat.No.	Product Name	Price
SHH372056	shRNA set against Rat PCSK9 (NM_199253.2)	Inquiry
SHH372052	shRNA set against Human PCSK9 (NM_174936.3)	Inquiry
SHR097808	shRNA set against Rat Pcsk9(NM_199253.2)	Inquiry
SHR097986	shRNA set against Mouse Pcsk9(NM_153565.2)	Inquiry

Cat.No.	Product Name	Price
RP00042	Recombinant Human PCSK9 (C-6His)	Inquiry
RP00137	Recombinant Human PCSK9 (D374Y,C-6His)	Inquiry
RP00153	Biotinylated Human PCSK9 (C-Avi)	Inquiry
RP00177	Recombinant Mouse PCSK9 (C-6His)	Inquiry
RP00182	Biotinylated Human PCSK9 (C-8His-HA-Avi)	Inquiry
RP00212	Recombinant Macaca nemestrina PCSK9 (C-6His)	Inquiry

Cat.No.	Product Name	Price
CDCL185642	Mouse PCSK9 ORF clone(NM_153565.2)	Inquiry
CDFR015050	Rat Pcsk9 cDNA Clone(NM_199253.2)	Inquiry
MiUTR1M-09018	PCSK9 miRNA 3'UTR clone	Inquiry
MiUTR1R-05693	PCSK9 miRNA 3'UTR clone	Inquiry
MiUTR3H-09469	PCSK9 miRNA 3'UTR clone	Inquiry
SKO0127	PCSK9 Validated sgRNA vector	Inquiry
CDCB157838	Human PCSK9 ORF clone (NM_174936.3)	Inquiry
CDCB194368	Rabbit PCSK9 ORF clone (XM_008265198.1)	Inquiry
CDCL185643	Rat PCSK9 ORF clone(NM_199253.2)	Inquiry

Detailed Information

The PCSK9 gene, located at 1p32.3, encodes Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9). After being synthesized in the liver, PCSK9 undergoes autocatalytic cleavage into its active form and is secreted into the bloodstream, where it binds to the low-density lipoprotein receptor (LDLR). PCSK9 interacts with the EGF-A domain of LDLR on the hepatocyte surface, forming a complex that is internalized into lysosomes, thereby preventing LDLR from recycling back to the cell membrane and reducing the clearance of LDL cholesterol (LDL-C).

Genetic studies reveal a dual role for PCSK9:

Gain-of-function mutations (e.g., D374Y): These mutations enhance the binding affinity between PCSK9 and LDLR, resulting in serum LDL-C levels exceeding 200 mg/dL and leading to familial hypercholesterolemia.
Loss-of-function mutations (e.g., R46L): These reduce LDLR degradation, lower LDL-C by approximately 28%, and significantly decrease the risk of coronary heart disease.

Beyond its classical role in lipid metabolism, PCSK9 also contributes to tumor metastasis by degrading low-density lipoprotein receptor-related protein 1 (LRP1). LRP1 normally acts as a transcriptional repressor by binding to the promoters of metastasis-related genes such as XAF1 and USP18. When PCSK9 binds and degrades LRP1, this repression is lifted, leading to overactivation of metastasis-promoting genes.

Figure 1. PCSK9 and LDLR biology in liver hepatocytes. (Hummelgaard S, et al., 2023)

Cardiovascular Disease and Targeted Therapy

PCSK9 monoclonal antibodies have marked a milestone in lipid-lowering therapies over the past decade:

Potent LDL-C Reduction: Alirocumab, administered at 75 mg biweekly, reduces LDL-C by 50.6% after 24 weeks compared to only 20.7% with ezetimibe.
Cardiovascular Benefits: The ODYSSEY OUTCOMES trial, which included 18,924 patients with acute coronary syndrome, demonstrated a 15% reduction in major cardiovascular events and a 15% decrease in all-cause mortality with Alirocumab treatment.

A 2024 Cell study revealed a novel oncogenic mechanism of PCSK9. The common germline variant rs562556 (V474I), present in 70% of the European population, encodes a mutant protein with enhanced LRP1-degrading capacity. This removes repression of XAF1 and USP18, promoting metastasis. Among breast cancer patients homozygous for the mutation, the 15-year distant metastasis rate reaches 22%, a tenfold increase compared to non-carriers. In animal models, PCSK9 knockout reduces pulmonary metastases by 80%, and the monoclonal antibody Evolocumab mimics this effect.

Expanding Clinical Indications

Based on these findings, the therapeutic potential of PCSK9 inhibitors extends beyond cardiovascular disease:

Metastasis Prevention: In a Phase II clinical trial, Evolocumab treatment in breast cancer patients carrying the rs562556 variant prolonged median metastasis-free survival by 15 months.
Neuroprotection: PCSK9 promotes neuronal apoptosis via degradation of LRP8/APOER2. In Alzheimer's disease models, Evolocumab reduced amyloid-beta (Aβ) deposition by 40%.

Challenges and Future Outlook

Current limitations include:

Administration Route: Monoclonal antibodies require subcutaneous injection every 2–4 weeks. Although siRNA-based Inclisiran is administered only twice a year, its long-term safety remains under investigation.
Cost-Effectiveness: Annual treatment costs exceed $5,000, limiting accessibility in low- and middle-income countries.

Future strategies focus on personalized therapy. Screening for rs562556 mutations could guide preventive treatment in breast cancer. Dual-target therapies—such as combining PCSK9 inhibitors with PD-1 antibodies—show synergistic effects in hepatocellular carcinoma models. With the oral small-molecule inhibitor MK-0616 entering Phase III clinical trials, the accessibility of PCSK9-targeted treatments is expected to improve significantly.

References:

Hummelgaard S, Vilstrup JP, Gustafsen C, et al. Targeting PCSK9 to tackle cardiovascular disease. Pharmacol Ther. 2023 Sep;249:108480.
Roth EM, Davidson MH. PCSK9 Inhibitors: Mechanism of Action, Efficacy, and Safety. Rev Cardiovasc Med. 2018;19(S1):S31-S46.

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