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Literature summary 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.
    View publication on PubMedView publication on EuropePMC

Application

EC Number Application Comment Organism
3.4.21.61 diagnostics plasma enzyme concentrations are predictive for 4-5 year major cardiovascular event rate, and enzyme serum concentrations correlate with cardiovascular risk Homo sapiens
3.4.21.61 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
3.4.21.61 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

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

Inhibitors

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

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
3.4.21.61 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
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3.4.21.61 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
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3.4.21.61 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
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3.4.21.61 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
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3.4.21.61 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
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Organism

EC Number Organism UniProt Comment Textmining
3.4.21.61 Homo sapiens Q8NBP7
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-
3.4.21.61 Mus musculus Q80W65
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-

Posttranslational Modification

EC Number Posttranslational Modification Comment Organism
3.4.21.61 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
3.4.21.61 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

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

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

Expression

EC Number Organism Comment Expression
3.4.21.61 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
3.4.21.61 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
3.4.21.61 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

EC Number General Information Comment Organism
3.4.21.61 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
3.4.21.61 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
3.4.21.61 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
3.4.21.61 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
3.4.21.61 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