Literature summary for 3.4.21.61 extracted from

Schulz, R.; Schlueter, K.D.; Laufs, U.
Molecular and cellular function of the proprotein convertase subtilisin/kexin type 9 (PCSK9) (2015), Basic Res. Cardiol., 110, 4.

Search for more literature for 3.4.21.61

Application

Application	Comment	Organism
diagnostics	plasma enzyme concentrations are predictive for 4-5 year major cardiovascular event rate, and enzyme serum concentrations correlate with cardiovascular risk	Homo sapiens
medicine	the proprotein convertase subtilisin/kexin type 9 has emerged as a promising treatment target to lower serum cholesterol, a major risk factor of cardiovascular diseases	Homo sapiens
medicine	the proprotein convertase subtilisin/kexin type 9 has emerged as a promising treatment target to lower serum cholesterol, a major risk factor of cardiovascular diseases	Mus musculus

Protein Variants

Protein Variants	Comment	Organism
C678X	a loss-of-function mutation that abolishes the release of the enzyme from the endoplasmic reticulum	Homo sapiens
C678X	a loss-of-function mutation that abolishes the release of the enzyme from the endoplasmic reticulum	Mus musculus
S462P	a loss-of-function mutation that abolishes the release of the enzyme from the endoplasmic reticulum	Homo sapiens
S462P	a loss-of-function mutation that abolishes the release of the enzyme from the endoplasmic reticulum	Mus musculus

Inhibitors

Inhibitors	Comment	Organism	Structure
additional information	clinical antibody studies, with alirocumab and evolocumab, overview	Homo sapiens

Localization

Localization	Comment	Organism	GeneOntology No.	Textmining
extracellular	secretion of the enzyme can be attenuated by annexin A2. Plasma concentration of the enzyme can be reduced by PPARalpha-dependent cleavage	Homo sapiens	-	-
Golgi apparatus	on its way through the Golgi and trans-Golgi complex, the enzyme co-localizes with the protein sortilin, in sortilin-knockout mice the plasma enzyme concentration is decreased, the protein-protein interaction is probably required for cellular secretion	Mus musculus	5794	-
Golgi apparatus	on its way through the Golgi and trans-Golgi complex, the enzyme co-localizes with the protein sortilin, the protein-protein interaction is probably required for cellular secretion	Homo sapiens	5794	-
additional information	the pro-form of the enzyme is synthesized in the endoplasmic reticulum. The binding of pro-PCSK9 to the low-density lipoprotein receptor in the endoplasmic reticulum supports the transport of the low-density lipoprotein receptor towards the Golgi complex. Trafficking of the pro-enzyme to the Golgi apparatus depends on the presence of the protein Sec24A. Within the Golgi, the pro-domain of the pro-enzyme is autocatalytically cleaved off, but remains non-covalently bound to the mature enzyme assisting the folding of the enzyme, and blocking its catalytic activity. Binding of pro-enzyme to the precursor form of the low-density lipoprotein receptor promotes PCSK9 autocatalytic cleavage	Homo sapiens	-	-
additional information	the pro-form of the enzyme is synthesized in the endoplasmic reticulum. The binding of pro-PCSK9 to the low-density lipoprotein receptor in the endoplasmic reticulum supports the transport of the low-density lipoprotein receptor towards the Golgi complex. Trafficking of the pro-enzyme to the Golgi apparatus depends on the presence of the protein Sec24A. Within the Golgi, the pro-domain of the pro-enzyme is autocatalytically cleaved off, but remains non-covalently bound to the mature enzyme assisting the folding of the enzyme, and blocking its catalytic activity. Binding of pro-enzyme to the precursor form of the low-density lipoprotein receptor promotes PCSK9 autocatalytic cleavage	Mus musculus	-	-

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	Q8NBP7	-	-
Mus musculus	Q80W65	-	-

Posttranslational Modification

Posttranslational Modification	Comment	Organism
proteolytic modification	the pro-form of the enzyme is synthesized in the endoplasmic reticulum. The binding of pro-PCSK9 to the low-density lipoprotein receptor in the endoplasmic reticulum supports the transport of the low-density lipoprotein receptor towards the Golgi complex. Trafficking of the pro-enzyme to the Golgi apparatus depends on the presence of the protein Sec24A. Within the Golgi, the pro-domain of the pro-enzyme is autocatalytically cleaved off, but remains non-covalently bound to the mature enzyme assisting the folding of the enzyme, and blocking its catalytic activity. Binding of pro-enzyme to the precursor form of the low-density lipoprotein receptor promotes PCSK9 autocatalytic cleavage	Homo sapiens
proteolytic modification	the pro-form of the enzyme is synthesized in the endoplasmic reticulum. The binding of pro-PCSK9 to the low-density lipoprotein receptor in the endoplasmic reticulum supports the transport of the low-density lipoprotein receptor towards the Golgi complex. Trafficking of the pro-enzyme to the Golgi apparatus depends on the presence of the protein Sec24A. Within the Golgi, the pro-domain of the pro-enzyme is autocatalytically cleaved off, but remains non-covalently bound to the mature enzyme assisting the folding of the enzyme, and blocking its catalytic activity. Binding of pro-enzyme to the precursor form of the low-density lipoprotein receptor promotes PCSK9 autocatalytic cleavage	Mus musculus

Source Tissue

Source Tissue	Comment	Organism	Textmining
central nervous system	-	Homo sapiens	-
central nervous system	-	Mus musculus	-
hepatocyte	-	Homo sapiens	-
hepatocyte	-	Mus musculus	-
intestine	-	Homo sapiens	-
intestine	-	Mus musculus	-
liver	-	Homo sapiens	-
liver	-	Mus musculus	-
pancreatic beta cell	-	Homo sapiens	-
pancreatic beta cell	-	Mus musculus	-
plasma	-	Homo sapiens	-
plasma	-	Mus musculus	-

Synonyms

Synonyms	Comment	Organism
NARC-1	-	Homo sapiens
PCSK type 9	-	Homo sapiens
PCSK type 9	-	Mus musculus
PCSK9	-	Homo sapiens
PCSK9	-	Mus musculus
proprotein convertase subtilisin/kexin type 9	-	Homo sapiens
proprotein convertase subtilisin/kexin type 9	-	Mus musculus

Expression

Organism	Comment	Expression
Homo sapiens	cholesteryl ester transfer protein inhibitors downregulate PCSK9 and LDLR expression through decreases in SREBP2 expression in hepatocytes. Glitazones, rapamycine, berberine, and resistin cause a reduction of enzyme expression via HNF1alpha reduction. Reduction of enzyme expression can be achieved by peroxisome proliferator-activated receptor alpha and activation of sterolresponse element binding protein 2. In HepG2 cells, hyperinsulinemia decreases the enzyme expression, an effect which is also observed in post-menopausal obese women	down
Homo sapiens	in healthy men 24 h hyperinsulinemia does not alter plasma the enzyme concentrations, and the enzyme expression is similar in normal, pre- and Typ2-diabetic patients	additional information
Homo sapiens	the enzyme is up-regulated during apoptosis of neurons. Statins and increase the transcription factor SREBP2, statins also the HNF1alpha expression, and fibrates increase PPAralpha, all leading to increased enzyme PCSK9 expression. Activation of enzyme expression can be mediated by activation of insulin receptors and subsequent activation of the sterolresponse element binding protein 1 and mammalian target of rapamycin pathways	up

General Information

General Information	Comment	Organism
malfunction	enzyme-knockout mice have more visceral adipose tissue. Enzyme-knockout mice carry more LDL receptor and less insulin in the pancreas, leading to hyperglycemia and glucose intolerance. beta-cell islets of enzyme-knockout mice inhibit signs of inflammation and apoptosis. This phenotype is modulated by gender and age	Mus musculus
malfunction	gain-of-function mutations of the enzyme are associated with hypercholesterolemia and increased risk of cardiovascular events, while loss-of-function mutations cause low-plasma LDL-C levels and a reduction of cardiovascular risk without known unwanted effects on individual health. Inhibition of PCSK9 alone and in addition to statins potently reduces serum LDL-C concentrations. Mutations of the enzyme leading to reduced expression and or function are associated with a reduced rate of coronary heart disease, myocardial infarction and overall cardiovascular events, an effect being more pronounced in colored as compared to white subjects	Homo sapiens
additional information	mutations in the EGF-A binding domain of the LDL receptor associated with familiar hypercholesterolemia increases enzyme PCSK9 binding. The formed PCSK9-LDL receptor complex is internalized again by clathrin-mediated endocytosis and the complex is then routed to the sorting endosome/lysosome. At acidic pH of the endosome/lysosome, an additional interaction between the ligand-binding domain of the LDL receptor and the C-terminal enzyme domain occurs and the enzyme remains bound to the LDL receptor, which fails to adopt a closed conformation which is required for LDL receptor recycling, mechanism, overview	Homo sapiens
physiological function	the enzyme binds to LDL-C receptors in hepatocytes promoting its autocatalytic cleavage. Regulation of PCSK9 gene expression by a number of transcription factors or cofactors, overview	Mus musculus
physiological function	the enzyme is important for brain development, especially the cerebellum. The enzyme reduces the hepatic uptake of LDL-C by increasing the endosomal and lysosomal degradation of LDL receptors. The regulation of the enzyme, its molecular function in lipid homeostasis and the emerging evidence on the extra-hepatic effects of the enzyme. High enzyme concentrations downregulate LDLR expression and favor the formation of oxidized (ox)-LDL. Development of atherosclerosis involves endothelial cell apoptosis and accumulation of foam cells, both of which can be triggered by oxidized LDL-C (oxLDL-C). The enzyme binds to LDL-C receptors in hepatocytes promoting its autocatalytic cleavage. Regulation of PCSK9 gene expression by a number of transcription factors or cofactors, overview	Homo sapiens

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Release 2023.1 (January 2023)