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FLASH GENE
Symbol PCSK9 contributors: mct - updated : 19-04-2017
HGNC name proprotein convertase subtilisin/kexin type 9
HGNC id 20001
Corresponding disease
HCHOLA3 hypercholesterolemia A3
Location 1p32.3      Physical location : 55.505.148 - 55.530.526
Synonym name
  • neural apoptosis regulated convertase 1
  • subtilisin/kexin-like protease PC9
  • proprotein convertase 9
  • Synonym symbol(s) FH3, NARC1, NARC-1, HCHOLA3, LDLCQ1, PC9
    EC.number 3.4.21.-
    DNA
    TYPE functioning gene
    STRUCTURE 39.91 kb     12 Exon(s)
    Genomic sequence alignment details
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    12 - 3731 72 692 - 2008 18052825
    11 - - - 634 expressed in multiple tissues, including liver, small intestine, prostate, uterus, brain, and adipose tissue 2008 18052825
  • also called PCSK9sv
  • had an in-frame deletion of the eighth exon of 58 amino acids
  • did not change the LDLR protein levels
  • EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinesmall intestine  highly
     liver   predominantly
    Respiratorylung     Homo sapiens
    Urinarykidney     Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Digestiveepithelial cell
    Digestivehepatocyte
    Nervousneuron
    Urinarymesenchymal cell
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a 30 AA signal peptide
  • a prodomain (AAs 3160), clearly playing a role for the normal function of PCSK9 (first containing AAs 3340, are responsible for the inhibitory effect of residues 3153 on PCSK9-mediated degradation of the LDLR)
  • a catalytic domain with the catalytic triad of aspartae(D), histidine (H), and serine (S)
  • a P domain
  • a hinge region,
  • a C-terminal Cys/His-rich domain of PCSK9 crucial in the regulation of PCSK9 activity , this cysteine-histidine rich domain is (CHRD) composed of three tightly packed modules named M1, M2, and M3
  • conjugated GlycoP
    isoforms Precursor cleaved N-terminal fragment remains associated with the mature protein and is necessary for its secretion, allowing it to circulate in the blood
    HOMOLOGY
    interspecies ortholog to murine Pcsk9
    Homologene
    FAMILY
  • proprotein convertase family of serine proteases
  • proteinase K family
  • proprotein convertase family
  • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,organelle,lysosome
    intracellular,cytoplasm,cytosolic,granule
    text lysosome-like vacuoles
    basic FUNCTION
  • playing a key role in cholesterol homeostasis through processing the sterol regulatory element-binding proteins
  • implicated in the differentiation of cortical neurons
  • plays a major role in determining plasma levels of LDL-C
  • acting as a natural inhibitor of the low density lipoprotein receptor pathway, and both genes are regulated by depletion of cholesterol cell content and statins, via sterol regulatory element-binding protein (SREBP)
  • having a general effect on the degradation of the LDLR family that emphasizes its major role in cholesterol and lipid homeostasis as well as brain development
  • enhancing the degradation of LDLR and its closest family members LRP8 and VLDLR, but not LRP1
  • play a major role in cholesterol homeostasis through enhanced degradation of the low-density lipoprotein receptor (LDLR) and possibly in neural development
  • plays an important role in regulating LDL receptor degradation
  • post-translationally regulates the number of cell-surface low density lipoprotein receptors (LDLR)
  • enhances the degradation of the LDLR in endosomes/lysosomes, upregulating LDL-cholesterol levels
  • degrade the low-density lipoprotein (LDL) receptor independently of its catalytic activity
  • binds to the epidermal growth factor domain A (EGFA) of low-density lipoprotein receptor (LDLR) and leads to its destruction
  • its function could reflect ancient roles in the fasting-feeding cycle and in linking lipoprotein metabolism with innate immunity
  • secreted protein that promotes degradation of cell surface LDL receptors (LDLRs) in selected cell types
  • PCSK9 might increase oxidized LDL uptake and impair macrophage-mediated reverse cholesterol transport, contributing to the development of atherosclerosis
  • plays a key role in regulating cholesterol homeostasis
  • may regulate apoptosis through mitochondrial pathway
  • OLR1 and PCSK9 positively influence each other's expression, especially during an inflammatory reaction
  • is a gene involved in lipid metabolism regulated by proinflammatory cytokine TNF in a SOCS3-dependent manner
  • play a role in impaired fetal growth by controlling fetal LDL-C metabolism, which seems to be dependent on gestational age and fetal gender
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    text cholesterol metabolism
    PATHWAY
    metabolism lipid/lipoprotein
    signaling
  • in the endocytic pathway, PCSK9 increases lysosomal degradation of the LDLR
  • a component
  • LDLR-PCSK9 complex is internalized via clathrin-mediated endocytosis and then routed to lysosomes via a mechanism that does not require ubiquitination and is distinct from the autophagy and proteosomal degradation pathways
  • INTERACTION
    DNA
    RNA
    small molecule metal binding,
  • Ca2+
  • protein
  • binds the extracellular domain of LDL receptor
  • interaction of PCSK9 with the LDLR EGF(A) domain occurring at the cell surface at neutral pH (enhanced PCSK9-LDLR interactions leading to gain-of-function phenotypes and hypercholesterolemia)
  • binding to LDLR is essential for the ensuing receptor-mediated endocytosis and is speculated to lock LDLR in a specific conformation that favors degradation in lysosomal compartment instead of recycling back to plasma membrane
  • PCSK9 binding to LDLR lead to its intracellular degradation instead of recycling back to cell membrane, and PCSK9-mediated LDLR degradation requires LDLR ubiquitination
  • HINFP is a co-activator in SREBF-mediated transactivation of PCSK9 gene expression
  • PCSK9 inhibits ENaC (SCNN1A, SCNN1B, SCNN1G) current by reducing the number of channels at the cell surface
  • BIRC2 acts on both secretion of PCSK9 and its lysosomal localization
  • enhances the cellular degradation of the LDL receptor (LDLR), leading to increased plasma LDL cholesterol
  • is capable of inducing degradation of LRP1, the latter is not an essential factor for LDLR regulation, but the LDLR effectively competes with LRP1 for PCSK9 activity
  • FOXO3 and SIRT6, two longevity genes, can reduce LDL-cholesterol levels through regulation of the PCSK9 gene
  • binding of WT- ectodomain (ED-LDLR) to pro-PCSK9 in the ER promotes autocatalytic cleavage of PCSK9, and autocatalytically cleaved PCSK9 acts as a chaperone to promote the exit of WT-ED-LDLR from the ER
  • plausible new role of ANXA2 in the reduction of PCSK9 protein levels via a translational mechanism
  • thyroid hormone (TH) reduces circulating PSCK9, thereby likely contributing to lower plasma LDL-cholesterol in hyperthyroidism
  • reduces hepatic low-density lipoprotein receptors (LDLRs) thereby increasing LDL-cholesterol (LDL-C)
  • binding of PCSK9 to HSP90B1 protects LDLR from degradation likely by preventing early binding of PCSK9 to LDLR within the ER
  • PAQR3 plays a pivotal role in controlling hepatic LDLR degradation and blood LDL-C level via modulating LDLR-PCSK9 interaction
  • cell & other
    REGULATION
    activated by pH (pH-dependent activation of PCSK9 represents a novel pathway to further activate PCSK9 in acidic endosomes)
    induced by inflammation (leading to increased LDL receptor degradation and decreasing LDL receptors thereby increasing serum LDL, which could have beneficial effects on host defense)
    inhibited by EGTA
    Other expression regulated by nutritional status and insulinemia
    ASSOCIATED DISORDERS
    corresponding disease(s) HCHOLA3
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional germinal mutation     loss of function
    nonsense mutations associated with low plasma levels of low-density lipoprotein cholesterol (LDL-C)
    constitutional       gain of function
    associated with hypercholesterolemia
    Susceptibility
  • to hypercholesterolemia
  • to low plasma levels of low-density lipoprotein cholesterol (LDL-C)
  • Variant & Polymorphism SNP , other
  • variants influencing the secretion of apoB-containing lipoproteins, and increasing in circulating LDL in heterozygous carriers
  • 3 SNPs associated with modest differences in plasma LDL-C levels
  • E670G variation associated with an increased incidence of coronary artery disease in men versus women
  • Candidate gene
    Marker
  • plasma PCSK9 levels may serve as a surrogate marker of hepatic SREBF2 activity in humans
  • PCSK9 could serve as a novel molecular biomarker for the non-invasive prenatal screening of neural tube defects (NTDs) and may be involved in the pathogenesis of NTDs at critical periods of fetal development
  • Therapy target
    SystemTypeDisorderPubmed
    miscelleaneousurinary 
    PCSK9 inhibitors may be beneficial in patients with nephrotic syndrome-associated hypercholesterolemia
    cardiovascularatheroma 
    attractive therapeutic target for LDL-C lowering, and for the treatment of cardiovascular disease
    cardiovascularatheroma 
    therapeutic target for the prevention of premature atherosclerosis and coronary heart disease
    cardiovascularatheroma 
    reducing PCSK9 expression or specific antibodies targeting and inhibiting PCSK9 interaction with the LDL receptor constitute very promising approaches to reducing cholesterol levels and coronary heart disease
    metabolismlipidcholesterol
    therapeutic PCSK9 inhibition may have vascular benefits secondary to LDL reduction
    cancerbrainglioma/neuroblstoma
    promising therapeutic strategy for the malignant glioma
    cardiovascularatheroma 
    silencing the expression/activity of PCSK9 is a new modality in the treatment of hypercholesterolemia and associated pathologies
    ANIMAL & CELL MODELS