PCSK9 proprotein convertase subtilisin/kexin type 9 [Homo sapiens (human)] - Gene

Summary

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Official Symbol: PCSK9provided by HGNC
Official Full Name: proprotein convertase subtilisin/kexin type 9provided by HGNC
Primary source: HGNC:20001
Locus tag: PSEC0052
See related: Ensembl:ENSG00000169174; HPRD:07080; MIM:607786; Vega:OTTHUMG00000008136
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: FH3; PC9; NARC1; LDLCQ1; NARC-1; HCHOLA3
Summary: 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 role in cholesterol homeostasis and may have a role in the differentiation of cortical neurons. Mutations in this gene have been associated with a third form of autosomal dominant familial hypercholesterolemia (HCHOLA3). [provided by RefSeq, Jul 2008]

Genomic context

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Location :: 1p32.3

Sequence :: Chromosome: 1; NC_000001.10 (55505149..55530526)

See PCSK9 in Epigenomics, MapViewer

Chromosome 1 - NC_000001.10 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Genomic Sequence

Go to nucleotideGraphics FASTA GenBank

Go to reference sequence details

Bibliography

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GeneRIFs: Gene References Into Functions What's a GeneRIF?

Association of PCSK9 with LDL particles in plasma lowers the ability of PCSK9 to bind to cell surface LDLRs, thereby blunting PCSK9-mediated LDLR degradation.
Title: Low density lipoprotein binds to proprotein convertase subtilisin/kexin type-9 (PCSK9) in human plasma and inhibits PCSK9-mediated low density lipoprotein receptor degradation.
There is no positive association of plasma PCSK9 with resistin in lean and moderately obese individuals.
Title: Relationship of proprotein convertase subtilisin-kexin type 9 levels with resistin in lean and obese subjects.
c-IAP1 acts on both secretion of PCSK9 and its lysosomal localization. The novel pathway described here will open new avenues for exploring novel disease treatments.
Title: c-IAP1 binds and processes PCSK9 protein: linking the c-IAP1 in a TNF-α pathway to PCSK9-mediated LDLR degradation pathway.
Furin-cleaved proprotein convertase subtilisin/kexin type 9 (PCSK9) is active and modulates low density lipoprotein receptor and serum cholesterol levels.
Title: Furin-cleaved proprotein convertase subtilisin/kexin type 9 (PCSK9) is active and modulates low density lipoprotein receptor and serum cholesterol levels.
M2 is dispensable for secretion, its presence is required for the extracellular activity of PCSK9 on cell surface LDLR.
Title: The M2 module of the Cys-His-rich domain (CHRD) of PCSK9 protein is needed for the extracellular low-density lipoprotein receptor (LDLR) degradation pathway.
The variant L10 of the leucine repeats in PCSK9 modulates the lipid-lowering effects of statins in heterozygous lial hypercholesterolemia.
Title: Leucine 10 allelic variant in signal peptide of PCSK9 increases the LDL cholesterol-lowering effect of statins in patients with familial hypercholesterolaemia.
AnxA2 acts as an endogenous regulator of PCSK9-induced LDLR degradation
Title: Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation.
Identify two new gain-of-function mutations of PCSK9 responsible for autosomal dominant hypercholesterolemia.
Title: Identification and characterization of new gain-of-function mutations in the PCSK9 gene responsible for autosomal dominant hypercholesterolemia.
analysis of loss- and gain-of-function PCSK9 variants with cleavage specificity, dominant negative effects, and low density lipoprotein receptor (LDLR) degradation
Title: Loss- and gain-of-function PCSK9 variants: cleavage specificity, dominant negative effects, and low density lipoprotein receptor (LDLR) degradation.
LDLR-PCSK9 complex is internalized via clathrin-mediated endocytosis and then routed to lysosomes
Title: Molecular characterization of proprotein convertase subtilisin/kexin type 9-mediated degradation of the LDLR.

Submit: New GeneRIF Correction See all (172)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Hypercholesterolemia, autosomal dominant, 3

MIM: 603776

Genetic Testing Registry

NHGRI GWAS Catalog

A genome-wide association study identifies susceptibility loci for Wilms tumor.

Biological, clinical and population relevance of 95 loci for blood lipids.

Common variants at 30 loci contribute to polygenic dyslipidemia.

Genetic determinants of statin-induced low-density lipoprotein cholesterol reduction: the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial.

Genetic variants influencing circulating lipid levels and risk of coronary artery disease.

Interactions

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Products	Interactant	Other Gene	Source	Pubs	Description
Q8NBP7	P01130	LDLR	HPRD	PubMed
Q8NBP7	Q8NBP7	PCSK9	HPRD	PubMed
BioGRID:129116	BioGRID:117154	BACE1	BioGRID	PubMed	Biochemical Activity; Reconstituted Complex
BioGRID:129116	BioGRID:113164	UBC	BioGRID	PubMed	Affinity Capture-MS

General gene information

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Markers

RH18483 (e-PCR)
- UniSTS:57345

D1S2892 (e-PCR)
- UniSTS:33591

PCSK9_1729 (e-PCR)
- UniSTS:277570

D1S2722 (e-PCR), detects polymorphism
- UniSTS:22405

RH65068 (e-PCR)
- UniSTS:219

Genotypes

See PCSK9 SNP Geneview Report
See PCSK9 SNP Genotype Report
See PCSK9 SNP Variation Viewer Report

Homology

Homologs of the PCSK9 gene: The PCSK9 gene is conserved in chimpanzee, Rhesus monkey, mouse, rat, chicken, zebrafish, M.oryzae, and N.crassa.
Map Viewer (Mouse, Rat)
OrthoDB: The Hierarchical Catalog of Eukaryotic Orthologs

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
apolipoprotein binding	ISS Inferred from Sequence or Structural Similarity more info
apolipoprotein receptor binding	IDA Inferred from Direct Assay more info	PubMed
identical protein binding	IEA Inferred from Electronic Annotation more info
low-density lipoprotein particle binding	ISS Inferred from Sequence or Structural Similarity more info
low-density lipoprotein particle receptor binding	IDA Inferred from Direct Assay more info	PubMed
low-density lipoprotein particle receptor binding	IPI Inferred from Physical Interaction more info	PubMed
protein binding	IPI Inferred from Physical Interaction more info	PubMed
protein self-association	IDA Inferred from Direct Assay more info	PubMed
serine-type endopeptidase activity	IDA Inferred from Direct Assay more info	PubMed
sodium channel inhibitor activity	IDA Inferred from Direct Assay more info
very-low-density lipoprotein particle binding	ISS Inferred from Sequence or Structural Similarity more info
very-low-density lipoprotein particle receptor binding	IDA Inferred from Direct Assay more info	PubMed

Process	Evidence Code	Pubs
apoptotic process	IEA Inferred from Electronic Annotation more info
cellular response to insulin stimulus	ISS Inferred from Sequence or Structural Similarity more info	PubMed
cellular response to starvation	ISS Inferred from Sequence or Structural Similarity more info	PubMed
cholesterol homeostasis	IMP Inferred from Mutant Phenotype more info	PubMed
cholesterol metabolic process	IEA Inferred from Electronic Annotation more info
induction of apoptosis	IEA Inferred from Electronic Annotation more info
kidney development	ISS Inferred from Sequence or Structural Similarity more info	PubMed
lipoprotein metabolic process	IEA Inferred from Electronic Annotation more info
liver development	ISS Inferred from Sequence or Structural Similarity more info	PubMed
low-density lipoprotein particle receptor catabolic process	IDA Inferred from Direct Assay more info	PubMed
lysosomal transport	IDA Inferred from Direct Assay more info	PubMed
negative regulation of catalytic activity	IEA Inferred from Electronic Annotation more info
negative regulation of low-density lipoprotein particle clearance	IDA Inferred from Direct Assay more info	PubMed
negative regulation of receptor recycling	IDA Inferred from Direct Assay more info	PubMed
neurogenesis	ISS Inferred from Sequence or Structural Similarity more info	PubMed
neuron differentiation	ISS Inferred from Sequence or Structural Similarity more info	PubMed
phospholipid metabolic process	IEA Inferred from Electronic Annotation more info
positive regulation of neuron apoptotic process	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of receptor internalization	IDA Inferred from Direct Assay more info	PubMed
protein autoprocessing	IDA Inferred from Direct Assay more info	PubMed
proteolysis	IBA Inferred from Biological aspect of Ancestor more info
regulation of low-density lipoprotein particle receptor catabolic process	IEA Inferred from Electronic Annotation more info
regulation of neuron apoptotic process	ISS Inferred from Sequence or Structural Similarity more info
regulation of receptor activity	IDA Inferred from Direct Assay more info	PubMed
triglyceride metabolic process	IEA Inferred from Electronic Annotation more info

Component	Evidence Code	Pubs
Golgi apparatus	IDA Inferred from Direct Assay more info	PubMed
cell surface	IDA Inferred from Direct Assay more info	PubMed
cytoplasm	IDA Inferred from Direct Assay more info
early endosome	IDA Inferred from Direct Assay more info	PubMed
endoplasmic reticulum	IDA Inferred from Direct Assay more info	PubMed
extracellular space	IDA Inferred from Direct Assay more info	PubMed
extrinsic to external side of plasma membrane	IC Inferred by Curator more info	PubMed
late endosome	IDA Inferred from Direct Assay more info	PubMed
lysosome	IDA Inferred from Direct Assay more info	PubMed
perinuclear region of cytoplasm	IDA Inferred from Direct Assay more info	PubMed
rough endoplasmic reticulum	IEA Inferred from Electronic Annotation more info

General protein information

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Preferred Names: proprotein convertase subtilisin/kexin type 9

Names: proprotein convertase subtilisin/kexin type 9; subtilisin/kexin-like protease PC9; neural apoptosis regulated convertase 1; convertase subtilisin/kexin type 9 preproprotein

NP_777596.2

EC 3.4.21.-

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_009061.1 RefSeqGene

Range

4930..30307

Download

GenBank, FASTA, Sequence Viewer (Graphics), LRG_275

mRNA and Protein(s)

NM_174936.3 → NP_777596.2 proprotein convertase subtilisin/kexin type 9 preproprotein

Status: REVIEWED

Source sequence(s)

AC091609, AL589790, BC042095, DA738424, EF692496

Consensus CDS

CCDS603.1

UniProtKB/Swiss-Prot

Q8NBP7

Related

ENSP00000303208, OTTHUMP00000009833, ENST00000302118, OTTHUMT00000022280

Conserved Domains (2) summary

cd04077
Location:156 – 421
Blast Score: 669

Peptidases_S8_PCSK9_ProteinaseK_like; Peptidase S8 family domain in ProteinaseK-like proteins

pfam05922
Location:77 – 152
Blast Score: 132

Inhibitor_I9; Peptidase inhibitor I9

RefSeqs of Annotated Genomes: Homo sapiens Annotation Release 104

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh37.p10 Primary Assembly

Genomic

NC_000001.10 Reference GRCh37.p10 Primary Assembly

Range

55505149..55530526

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate HuRef

Genomic

AC_000133.1 Alternate HuRef

Range

53618200..53643557

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate CHM1_1.0

Genomic

NC_018912.1 Alternate CHM1_1.0

Range

55581548..55606919

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Nucleotide		Protein
Heading	Accession and Version	Protein
genomic	ABBA01074699.1 (104396..129753)	None
genomic	AC091609.2 (163563..183517)	None
genomic	AL589790.22 (39351..44075)	None
genomic	AMYH01000641.1 (217402..242773)	None
genomic	AX127530.1	CAC38896.1
genomic	AX207686.1	CAC60361.1
genomic	AY829011.1	AAV67948.1
genomic	CH471059.2	EAX06660.1
genomic	FJ525880.1	ACN81318.1
mRNA	AK075365.1	BAC11572.1
mRNA	AK122717.1	None
mRNA	AK124635.1	BAC85910.1
mRNA	AK293870.1	BAG57260.1
mRNA	AK297473.1	BAG59894.1
mRNA	BC042095.1	None
mRNA	DA738424.1	None
mRNA	EF692496.1	ABV59216.1
other-genetic	BC166619.1	AAI66619.1