Homo sapiens Protein: PCSK9
InnateDB Protein IDBP-99084.6
Last Modified 2014-10-13 [Report errors or provide feedback]
Gene Symbol PCSK9
Protein Name proprotein convertase subtilisin/kexin type 9
Species Homo sapiens
Ensembl Protein ENSP00000303208
InnateDB Gene IDBG-99082 (PCSK9)
Protein Structure
UniProt Annotation
Function Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways. {ECO:0000269PubMed:17461796, ECO:0000269PubMed:18039658, ECO:0000269PubMed:18197702, ECO:0000269PubMed:18660751, ECO:0000269PubMed:22074827, ECO:0000269PubMed:22493497, ECO:0000269PubMed:22580899}.
Subcellular Localization Cytoplasm. Secreted. Endosome. Lysosome. Cell surface. Endoplasmic reticulum. Golgi apparatus. Note=Autocatalytic cleavage is required to transport it from the endoplasmic reticulum to the Golgi apparatus and for the secretion of the mature protein. Localizes to the endoplasmic reticulum in the absence of LDLR and colocalizes to the cell surface and to the endosomes/lysosomes in the presence of LDLR. The sorting to the cell surface and endosomes is required in order to fully promote LDLR degradation.
Disease Associations Hypercholesterolemia, autosomal dominant, 3 (HCHOLA3) [MIM:603776]: A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins. {ECO:0000269PubMed:12730697}. Note=The disease is caused by mutations affecting the gene represented in this entry.
Tissue Specificity Expressed in neuro-epithelioma, colon carcinoma, hepatic and pancreatic cell lines, and in Schwann cells.
Number of Interactions This gene and/or its encoded proteins are associated with 6 experimentally validated interaction(s) in this database.
Experimentally validated
Total 6 [view]
Protein-Protein 6 [view]
Protein-DNA 0
Protein-RNA 0
Gene Ontology

Molecular Function
Accession GO Term
GO:0004252 serine-type endopeptidase activity
GO:0005515 protein binding
GO:0019871 sodium channel inhibitor activity
GO:0030169 low-density lipoprotein particle binding
GO:0034185 apolipoprotein binding
GO:0034189 very-low-density lipoprotein particle binding
GO:0034190 apolipoprotein receptor binding
GO:0043621 protein self-association
GO:0044822 poly(A) RNA binding
GO:0050750 low-density lipoprotein particle receptor binding
GO:0070326 very-low-density lipoprotein particle receptor binding
Biological Process
GO:0001822 kidney development
GO:0001889 liver development
GO:0001920 negative regulation of receptor recycling
GO:0002092 positive regulation of receptor internalization
GO:0006508 proteolysis
GO:0006641 triglyceride metabolic process
GO:0006644 phospholipid metabolic process
GO:0006915 apoptotic process
GO:0007041 lysosomal transport
GO:0008203 cholesterol metabolic process
GO:0009267 cellular response to starvation
GO:0010469 regulation of receptor activity
GO:0010989 negative regulation of low-density lipoprotein particle clearance
GO:0016485 protein processing
GO:0016540 protein autoprocessing
GO:0022008 neurogenesis
GO:0030182 neuron differentiation
GO:0032799 low-density lipoprotein receptor particle metabolic process
GO:0032802 low-density lipoprotein particle receptor catabolic process
GO:0032803 regulation of low-density lipoprotein particle receptor catabolic process
GO:0032869 cellular response to insulin stimulus
GO:0042157 lipoprotein metabolic process
GO:0042632 cholesterol homeostasis
GO:0043523 regulation of neuron apoptotic process
GO:0043525 positive regulation of neuron apoptotic process
Cellular Component
GO:0005576 extracellular region
GO:0005615 extracellular space
GO:0005737 cytoplasm
GO:0005764 lysosome
GO:0005769 early endosome
GO:0005770 late endosome
GO:0005783 endoplasmic reticulum
GO:0005791 rough endoplasmic reticulum
GO:0005794 Golgi apparatus
GO:0005886 plasma membrane
GO:0009986 cell surface
GO:0030134 ER to Golgi transport vesicle
GO:0031232 extrinsic component of external side of plasma membrane
GO:0048471 perinuclear region of cytoplasm
Protein Structure and Domains
InterPro IPR000209 Peptidase S8/S53 domain
IPR009020 Proteinase inhibitor, propeptide
IPR010259 Proteinase inhibitor I9
IPR015500 Peptidase S8, subtilisin-related
PFAM PF00082
Post-translational Modifications
SwissProt Q8NBP7
PhosphoSite PhosphoSite-Q8NBP7
UniProt Splice Variant
Entrez Gene 255738
UniGene Hs.18844
RefSeq NP_777596
OMIM 607786
HPRD 07080
EMBL AC091609 AK075365 AK124635 AL589790 AX127530 AY829011 CH471059 EF692496 FJ525880
GenPept AAV67948 ABV59216 ACN81318 BAC11572 BAC85910 CAC38896 CAI17845 EAX06660