PCSK9: Polycystic Ovarian Syndrome Database

Gene Information

Gene Symbol

PCSK9

Aliases

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

Entrez Gene ID

255738

Gene Name

Proprotein convertase subtilisin/kexin type 9

Chromosomal Location

1p32.3

HGNC ID

HGNC:20001

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]

RefSeq DNA

NG_009061.1

RefSeq mRNA

NR_110451.1, NM_174936.4, NM_174936.3

e!Ensembl

Gene	ENSG00000169174
Transcript	ENST00000302118
Protein	ENSP00000303208

Gene Ontology (GO)

Show/Hide all(45 )

GO ID	Ontology	Function	Evidence	Reference
GO:0001822	Biological process	Kidney development	ISS	12552133
GO:0001889	Biological process	Liver development	ISS	12552133
GO:0001920	Biological process	Negative regulation of receptor recycling	IDA	17452316, 22848640
GO:0002092	Biological process	Positive regulation of receptor internalization	IDA	17328821
GO:0007041	Biological process	Lysosomal transport	IDA	17452316
GO:0009267	Biological process	Cellular response to starvation	ISS	16407292
GO:0010469	Biological process	Regulation of signaling receptor activity	IDA	17328821
GO:0010989	Biological process	Negative regulation of low-density lipoprotein particle clearance	IDA	17328821, 22848640
GO:0016540	Biological process	Protein autoprocessing	IDA	14622975
GO:0022008	Biological process	Neurogenesis	ISS	12552133
GO:0030182	Biological process	Neuron differentiation	ISS	12552133
GO:0032802	Biological process	Low-density lipoprotein particle receptor catabolic process	IDA	16912035, 18197702
GO:0032805	Biological process	Positive regulation of low-density lipoprotein particle receptor catabolic process	IDA	22848640
GO:0032869	Biological process	Cellular response to insulin stimulus	ISS	12552133
GO:0042632	Biological process	Cholesterol homeostasis	IMP	17170371
GO:0043525	Biological process	Positive regulation of neuron apoptotic process	IMP	17051583
GO:1905596	Biological process	Negative regulation of low-density lipoprotein particle receptor binding	IDA	22848640
GO:1905598	Biological process	Negative regulation of low-density lipoprotein receptor activity	IDA	22848640
GO:1905601	Biological process	Negative regulation of receptor-mediated endocytosis involved in cholesterol transport	IDA	22848640
GO:2000650	Biological process	Negative regulation of sodium ion transmembrane transporter activity	IDA	22493497
GO:0005615	Cellular component	Extracellular space	IBA	21873635
GO:0005615	Cellular component	Extracellular space	IDA	12552133, 16912035, 17080197
GO:0005737	Cellular component	Cytoplasm	IDA	22580899
GO:0005764	Cellular component	Lysosome	IDA	17461796, 18039658
GO:0005769	Cellular component	Early endosome	IDA	17461796
GO:0005770	Cellular component	Late endosome	IDA	17461796, 18039658
GO:0005783	Cellular component	Endoplasmic reticulum	IDA	17461796
GO:0005794	Cellular component	Golgi apparatus	IDA	17461796
GO:0005886	Cellular component	Plasma membrane	IDA	18799458
GO:0009986	Cellular component	Cell surface	IDA	17461796
GO:0031232	Cellular component	Extrinsic component of external side of plasma membrane	IC	17328821
GO:0048471	Cellular component	Perinuclear region of cytoplasm	IDA	18039658
GO:1990666	Cellular component	PCSK9-LDLR complex	IDA	22848640
GO:1990667	Cellular component	PCSK9-AnxA2 complex	IDA	22848640
GO:0003723	Molecular function	RNA binding	HDA	22658674
GO:0004252	Molecular function	Serine-type endopeptidase activity	IBA	21873635
GO:0004252	Molecular function	Serine-type endopeptidase activity	IDA	12552133
GO:0005515	Molecular function	Protein binding	IPI	17461796, 18799458, 22081141, 22493497, 22580899, 22848640, 25613181
GO:0019871	Molecular function	Sodium channel inhibitor activity	IDA	22493497
GO:0030547	Molecular function	Receptor inhibitor activity	IDA	22848640
GO:0034190	Molecular function	Apolipoprotein receptor binding	IDA	18039658
GO:0043621	Molecular function	Protein self-association	IDA	18197702
GO:0050750	Molecular function	Low-density lipoprotein particle receptor binding	IDA	17080197
GO:0050750	Molecular function	Low-density lipoprotein particle receptor binding	IPI	17452316, 22848640
GO:0070326	Molecular function	Very-low-density lipoprotein particle receptor binding	IDA	18039658

Protein Information

Protein Name

Proprotein convertase subtilisin/kexin type 9, convertase subtilisin/kexin type 9 preproprotein, neural apoptosis regulated convertase 1, subtilisin/kexin-like protease PC9

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 (PubMed:18039658). 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 (PubMed:18799458, PubMed:17461796, PubMed:18197702, PubMed:22074827). 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 (PubMed:18660751). 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.

Refseq Proteins

, NP_777596.2

UniProt

Q8NBP7

PDB

2W2M, 2W2N, 2W2O, 2W2P, 2W2Q, 3BPS, 3GCW, 3GCX, 3M0C, 3P5B, 3P5C, 4NE9, 2P4E, 2PMW, 2QTW, 2XTJ, 3H42, 3SQO, 4K8R, 4NMX, 4OV6, 5OCA, 5VL7, 5VLA, 5VLH, 5VLK, 5VLL, 5VLP, 6E4Y, 6E4Z, 6F5G, 6MV5

Pfam

Pfam Accession	Pfam ID
PF05922	Inhibitor_I9
PF00082	Peptidase_S8

PCSK9

Hyperhomocysteinemia and hyperandrogenemia share PCSK9-LDLR pathway to disrupt lipid homeostasis in PCOS.