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

    Gene ID: 255738, updated on 25-May-2017
    Official Symbol
    PCSK9provided by HGNC
    Official Full Name
    proprotein convertase subtilisin/kexin type 9provided by HGNC
    Primary source
    HGNC:HGNC:20001
    See related
    Ensembl:ENSG00000169174 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 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]
    Orthologs
    Location:
    1p32.3
    Exon count:
    13
    Annotation release Status Assembly Chr Location
    108 current GRCh38.p7 (GCF_000001405.33) 1 NC_000001.11 (55039476..55064853)
    105 previous assembly GRCh37.p13 (GCF_000001405.25) 1 NC_000001.10 (55505149..55530526)

    Chromosome 1 - NC_000001.11Genomic Context describing neighboring genes Neighboring gene transmembrane protein 61 Neighboring gene barttin CLCNK type accessory beta subunit Neighboring gene ubiquitin specific peptidase 24 Neighboring gene uncharacterized LOC100507634

    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Jun 15 11:32:44 2016

    GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

    Professional guidelines

    Description
    Professional guideline
    ACMG 2013

    The ACMG recommends that laboratories performing clinical sequencing seek and report mutations in PCSK9 that are pathogenic or expected to be pathogenic.

    GuidelinePubMed

    Associated conditions

    Description Tests
    Hypercholesterolemia, autosomal dominant, 3
    MedGen: C1863551 OMIM: 603776 GeneReviews: Familial Hypercholesterolemia
    Compare labs

    Copy number response

    Description
    Copy number response
    Triplosensitivity

    No evidence available (Last evaluated (2015-12-17)

    ClinGen Genome Curation Page
    Haploinsufficency

    Dosage sensitivity unlikely (Last evaluated (2015-12-17)

    ClinGen Genome Curation PagePubMed

    NHGRI GWAS Catalog

    Description
    A genome-wide association study identifies susceptibility loci for Wilms tumor.
    NHGRI GWA Catalog
    Biological, clinical and population relevance of 95 loci for blood lipids.
    NHGRI GWA Catalog
    Common variants at 30 loci contribute to polygenic dyslipidemia.
    NHGRI GWA Catalog
    Discovery and refinement of loci associated with lipid levels.
    NHGRI GWA Catalog
    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.
    NHGRI GWA Catalog
    Genetic variants influencing circulating lipid levels and risk of coronary artery disease.
    NHGRI GWA Catalog
    Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants.
    NHGRI GWA Catalog
    Genome-wide association study identifies multiple loci influencing human serum metabolite levels.
    NHGRI GWA Catalog
    Genome-wide characterization of shared and distinct genetic components that influence blood lipid levels in ethnically diverse human populations.
    NHGRI GWA Catalog
    Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease.
    NHGRI GWA Catalog
    Newly identified loci that influence lipid concentrations and risk of coronary artery disease.
    NHGRI GWA Catalog
    Novel Loci for metabolic networks and multi-tissue expression studies reveal genes for atherosclerosis.
    NHGRI GWA Catalog
    Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans.
    NHGRI GWA Catalog
    • Evolocumab Mechanism, organism-specific biosystem (from WikiPathways)
      Evolocumab Mechanism, organism-specific biosystemEvolocumab (Repatha) is an injectable monoclonal antibody that effectively reduces LDL-Cholesterol levels. A limited quantity of LDL-Cholesterol is extracted from circulative blood when PCSK9-bound L...
    • LDL-mediated lipid transport, organism-specific biosystem (from REACTOME)
      LDL-mediated lipid transport, organism-specific biosystemLDL (low density lipoproteins) are complexes of a single molecule of apoprotein B-100 (apoB-100) non-covalently associated with triacylglycerol, free cholesterol, cholesterol esters, and phospholipid...
    • Lipid digestion, mobilization, and transport, organism-specific biosystem (from REACTOME)
      Lipid digestion, mobilization, and transport, organism-specific biosystemProcesses annotated here include the digestion of dietary lipids, sterol uptake, the formation and turnover of lipoproteins (chylomicrons, VLDL, LDL, and HDL), and the mobilization of fatty acids thr...
    • Lipoprotein metabolism, organism-specific biosystem (from REACTOME)
      Lipoprotein metabolism, organism-specific biosystemBecause of their hydrophobicity, lipids are found in the extracellular spaces of the human body primarily in the form of lipoprotein complexes. Chylomicrons form in the small intestine and transport ...
    • Metabolism, organism-specific biosystem (from REACTOME)
      Metabolism, organism-specific biosystemMetabolic processes in human cells generate energy through the oxidation of molecules consumed in the diet and mediate the synthesis of diverse essential molecules not taken in the diet as well as th...
    • Metabolism of lipids and lipoproteins, organism-specific biosystem (from REACTOME)
      Metabolism of lipids and lipoproteins, organism-specific biosystemLipids are hydrophobic but otherwise chemically diverse molecules that play a wide variety of roles in human biology. They include ketone bodies, fatty acids, triacylglycerols, phospholipids and sphi...
    • Proprotein convertase subtilisin/kexin type 9 (PCSK9) mediated LDL receptor degradation, organism-specific biosystem (from WikiPathways)
      Proprotein convertase subtilisin/kexin type 9 (PCSK9) mediated LDL receptor degradation, organism-specific biosystemExogenously, circulating PCSK9 (Proprotein convertase subtilisin/kexin type 9) protein binds to LDLR (LDL receptor). Once internalized into the liver cell, the PCSK9 protein directs the LDLR to the l...
    • VLDL interactions, organism-specific biosystem (from REACTOME)
      VLDL interactions, organism-specific biosystemVery-low-density lipoprotein (VLDL) is a lipoprotein made by the liver (Gibbons et al. 2004) and is one of the five major groups of lipoproteins (chylomicrons, VLDL, LDL, IDL and HDL) that enable fat...
    • VLDLR internalisation and degradation, organism-specific biosystem (from REACTOME)
      VLDLR internalisation and degradation, organism-specific biosystemThe steps involved in proprotein convertase PCSK9-induced degradation of VLDLR are described here (Poirier et al. 2008).
    Products Interactant Other Gene Complex Source Pubs Description

    Markers

    Homology

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    RNA binding IDA
    Inferred from Direct Assay
    more info
    PubMed 
    apolipoprotein binding ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    apolipoprotein receptor binding IDA
    Inferred from Direct Assay
    more info
    PubMed 
    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 
    receptor inhibitor activity 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
    PubMed 
    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 protein metabolic process TAS
    Traceable Author Statement
    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
     
    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 clearance TAS
    Traceable Author Statement
    more info
     
    low-density lipoprotein particle receptor catabolic process IDA
    Inferred from Direct Assay
    more info
    PubMed 
    low-density lipoprotein particle receptor catabolic process TAS
    Traceable Author Statement
    more info
     
    lysosomal transport IDA
    Inferred from Direct Assay
    more info
    PubMed 
    negative regulation of low-density lipoprotein particle clearance IDA
    Inferred from Direct Assay
    more info
    PubMed 
    negative regulation of low-density lipoprotein particle receptor binding IDA
    Inferred from Direct Assay
    more info
    PubMed 
    negative regulation of low-density lipoprotein receptor activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    negative regulation of receptor recycling IDA
    Inferred from Direct Assay
    more info
    PubMed 
    negative regulation of receptor-mediated endocytosis involved in cholesterol transport IDA
    Inferred from Direct Assay
    more info
    PubMed 
    negative regulation of sodium ion transmembrane transporter activity 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 low-density lipoprotein particle receptor catabolic process IDA
    Inferred from Direct Assay
    more info
    PubMed 
    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 
    post-translational protein modification TAS
    Traceable Author Statement
    more info
     
    protein autoprocessing IDA
    Inferred from Direct Assay
    more info
    PubMed 
    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
    ER to Golgi transport vesicle IEA
    Inferred from Electronic Annotation
    more info
     
    Golgi apparatus IDA
    Inferred from Direct Assay
    more info
    PubMed 
    PCSK9-AnxA2 complex IDA
    Inferred from Direct Assay
    more info
    PubMed 
    PCSK9-LDLR complex 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
    PubMed 
    early endosome IDA
    Inferred from Direct Assay
    more info
    PubMed 
    endolysosome membrane TAS
    Traceable Author Statement
    more info
     
    endoplasmic reticulum IDA
    Inferred from Direct Assay
    more info
    PubMed 
    endoplasmic reticulum lumen TAS
    Traceable Author Statement
    more info
     
    extracellular region TAS
    Traceable Author Statement
    more info
     
    extracellular space IDA
    Inferred from Direct Assay
    more info
    PubMed 
    extrinsic component of external side of plasma membrane IC
    Inferred by Curator
    more info
    PubMed 
    late endosome IDA
    Inferred from Direct Assay
    more info
    PubMed 
    lysosomal membrane TAS
    Traceable Author Statement
    more info
     
    lysosome IDA
    Inferred from Direct Assay
    more info
    PubMed 
    perinuclear region of cytoplasm IDA
    Inferred from Direct Assay
    more info
    PubMed 
    plasma membrane IDA
    Inferred from Direct Assay
    more info
    PubMed 
    rough endoplasmic reticulum IEA
    Inferred from Electronic Annotation
    more info
     
    Preferred Names
    proprotein convertase subtilisin/kexin type 9
    Names
    convertase subtilisin/kexin type 9 preproprotein
    neural apoptosis regulated convertase 1
    subtilisin/kexin-like protease PC9
    NP_777596.2

    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

    1. NG_009061.1 RefSeqGene

      Range
      4930..30307
      Download
      GenBank, FASTA, Sequence Viewer (Graphics), LRG_275

    mRNA and Protein(s)

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

      See identical proteins and their annotated locations for NP_777596.2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the longer transcript and encodes the functional protein.
      Source sequence(s)
      AC091609, AL589790, BC042095, DA738424, EF692496
      Consensus CDS
      CCDS603.1
      UniProtKB/Swiss-Prot
      Q8NBP7
      Related
      ENSP00000303208.5, OTTHUMP00000009833, ENST00000302118.5, OTTHUMT00000022280
      Conserved Domains (3) summary
      cd04077
      Location:156421
      Peptidases_S8_PCSK9_ProteinaseK_like; Peptidase S8 family domain in ProteinaseK-like proteins
      pfam00082
      Location:180422
      Peptidase_S8; Subtilase family
      pfam05922
      Location:77149
      Inhibitor_I9; Peptidase inhibitor I9

    RNA

    1. NR_110451.1 RNA Sequence

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) uses an alternate 5' terminal exon, lacks two internal exons, and uses an alternate splice site in an internal exon, compared to variant 1. This variant is represented as non-coding because the predicted protein does not meet RefSeq quality criteria.
      Source sequence(s)
      AC091609, AK297473, BC042095

    RefSeqs of Annotated Genomes: Homo sapiens Annotation Release 108 details...Open this link in a new tab

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

    Reference GRCh38.p7 Primary Assembly

    Genomic

    1. NC_000001.11 Reference GRCh38.p7 Primary Assembly

      Range
      55039476..55064853
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    Alternate CHM1_1.1

    Genomic

    1. NC_018912.2 Alternate CHM1_1.1

      Range
      55621314..55646685
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)
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