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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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_174936 12 - 3731 NP_777596 72 692 - 2008 18052825 variant 2 11 - - isoform 2 - 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)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive intestine small intestine     highly   liver       predominantly Respiratory lung         Homo sapiens Urinary kidney         Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Digestive epithelial cell Digestive hepatocyte Nervous neuron Urinary mesenchymal cell

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a 30 AA signal peptide
	a prodomain (AAs 31–60), clearly playing a role for the normal function of PCSK9 (first containing AAs 33–40, are responsible for the inhibitory effect of residues 31–53 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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed miscelleaneous urinary   PCSK9 inhibitors may be beneficial in patients with nephrotic syndrome-associated hypercholesterolemia cardiovascular atheroma   attractive therapeutic target for LDL-C lowering, and for the treatment of cardiovascular disease cardiovascular atheroma   therapeutic target for the prevention of premature atherosclerosis and coronary heart disease cardiovascular atheroma   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 metabolism lipid cholesterol therapeutic PCSK9 inhibition may have vascular benefits secondary to LDL reduction cancer brain glioma/neuroblstoma promising therapeutic strategy for the malignant glioma cardiovascular atheroma   silencing the expression/activity of PCSK9 is a new modality in the treatment of hypercholesterolemia and associated pathologies

ANIMAL & CELL MODELS