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malfunction
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at t = 585 min, PCSK9-/- hepatocytes exhibit 90% less activity than wild-type
malfunction
cells with lower PCSK9 expression and secretion have a low density lipoprotein binding activity augmented by 200%
malfunction
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in addition to its effect on LDL-cholesterol, PCSK9 deficiency may protect against cardiovascular disease by reducing postprandial triglyceridemia: PCSK9-deficient mice show a dramatically decreased postprandial triglyceridemia compared with their wild-type littermates. Intestinal triglyceride output is not quantitatively modified by PCSK9 deletion. PCSK9-/- mice present with a significant reduction of lymphatic apoB secretion compared to PCSK9+/+ mice. PCSK9-/- mice secrete larger triglyceride-rich lipoprotein than wild-type littermates. PCSK9-deficient mice have an increased ability to clear chylomicrons compared to wild-type littermates. The dramatic reduction of postprandial lipemia in PCSK9-/- mice results from the combination of various effects, including the intestinal secretion of larger chylomicrons, and their higher hepatic clearance rate
malfunction
D374Y is a naturally occurring gain-of-function mutation causing severe hypercholesterolaemia in humans due to a significantly decreased dissociation rate constant, whereas the mutation does not affect the association rate constant
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
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
malfunction
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lack of PCSK6-dependent corin activation leads to hypertension. PCSK6-mediated processing of corin is reduced in the presence of corin variants T555I and Q568P previously associated to hypertension and to heart disease
metabolism
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an interaction between the prodomain and C-terminal domain regulates the secretion of PCSK9
metabolism
PCSK6 can activate NF-kappaB, STAT3 and ERK1/2 signaling pathways in vitro to enhance cell proliferation, migration, invasion and inflammation in rheumatoid arthritis synovial fibroblast (RASF) cells. Recombinant enzyme rhPCSK6 promotes the production of pro-inflammatory factors in RASFs. Pro?inflammatory cytokines serve promixadnent roles in rheumatoid arthritis. RASFs can secrete interleukin (IL)-1alpha, IL-1beta, IL-6, IL-17, and TNF-alpha
physiological function
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high level of activity in wild-type PCSK9+/+ hepatocytes. At t = 585 min, the activity of 20 microg of total hepatocyte lysates is 360% higher than that of 10 microg of purified protein
physiological function
PCSK9 binds to the low density lipoprotein receptor and leads to low density lipoprotein receptor degradation and inhibition of plasma low density lipoprotein cholesterol clearance. PCSK9 C-terminal domain contributes to its inhibition of low density lipoprotein receptor function mainly through its role in the cellular uptake of PCSK9 and low-density lipoprotein receptor complex
physiological function
PCSK9 plays a role in the small intestine
physiological function
PCSK9-induced upregulation of cholesterol biosynthesis genes results from intracellular cholesterol starvation. PCSK9 affects metabolic pathways beyond cholesterol metabolism in Hep-G2 cells. Pathways that are presumably regulated by PCSK9 and are independent of its effects on cholesterol uptake include protein ubiquitination, xenobiotic metabolism, cell cycle, and inflammation and stress response
physiological function
proprotein convertase subtilisin-kexin type 9 is a key regulator of low density lipoprotein receptor processing, and affects especially intermediate density lipoproteins. The enzyme pathway may affect plasma triglycerides via effects on the metabolism of triglyceriderich LDL particles
physiological function
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proprotein convertase subtilisin/kexin 9 enhances the degradation of the LDL receptor in endosomes/lysosomes, resulting in increased circulating LDLc. The enzyme can also mediate the degradation of LDL receptor lacking its cytosolic tail, the transmembrane-domain of the receptor is not involved, but a lysosomal-targeting factor, overview. Role for the enzyme in enhancing tumor metastasis, consequences of enzyme inhibition for lowering LDLc and tumor metastasis
physiological function
proprotein convertase subtilisin/kexin 9 enhances the degradation of the LDL receptor in endosomes/lysosomes, resulting in increased circulating LDLc. The enzyme can also mediate the degradation of LDL receptor lacking its cytosolic tail, the transmembrane-domain of the receptor is not involved, but a lysosomal-targeting factor.overview. The LDL receptor is insensitive to the enzyme in murine B16F1 melanoma cells, but the enzyme is able to induce degradation of the low density lipoprotein receptor-related protein 1, suggesting distinct targeting mechanisms for these receptors. Role for the enzyme in enhancing tumor metastasis
physiological function
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proprotein convertase subtilisin/kexin 9 enhances the degradation of the LDL receptor in endosomes/lysosomes, resulting in increased circulating LDLc. The enzyme is capable of acting upon the LDL receptor in CHO 13-5-1 cells lacking LRP-1. It also acts on LRP-1 in the absence of the LDL receptor in CHO-A7 cells, where re-introduction of the LDL receptor leads to reduced enzyme-mediated degradation of LRP-1
physiological function
proprotein convertase subtilisin/kexin 9 regulates plasma LDL cholesterol levels by regulating the degradation of LDL receptors, furin resistance is the underlying molecular mechanism for the gain of function phenotype
physiological function
proprotein convertase subtilisin/kexin type 9 negatively regulates the low-density lipoprotein (LDL) receptor in hepatocytes and plays an important role in controlling circulating levels of LDL-cholesterol. It interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor, resulting in results in increased secretion of apoB-containing lipoproteins and increased levels of cholesterol and triacylglycerol. PCSK9/apoB interaction results in increased production of apoB, possibly through the inhibition of intracellular apoB degradation via the autophagosome/lysosome pathway. Role for the enzyme in shuttling between apoB and LDLR-receptor
physiological function
proprotein convertase subtilisin/kexin type 9 negatively regulates the low-density lipoprotein (LDL) receptor in hepatocytes and plays an important role in controlling circulating levels of LDL-cholesterol. It interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor, resulting in results in increased secretion of apoB-containing lipoproteins and increased levels of cholesterol and triacylglycerol. PCSK9/apoB interaction results in increased production of apoB, possibly through the inhibition of intracellular apoB degradation via the autophagosome/lysosome pathway. Role for the enzyme in shuttling between apoB and LDLR-receptor
physiological function
residues of the prodomain C-terminus regulate proteolysis and secretion independently. The prodomain C-terminus regulates protein secretion but is not required for catalytic domain binding
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
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
physiological function
the enzyme promotes the degradation of the hepatic low density lipoprotein receptor. The C-terminal domain of the enzyme is unlikely to be involved in a direct extracellular interaction with the LDL-receptor
physiological function
proprotein convertase subtilisin/kexin type 6 promotes in vitro proliferation, migration and inflammatory cytokine secretion of synovial fibroblast-like cells from rheumatoid arthritis via nuclear-kappaB, signal transducer and activator of transcription 3 and activator of transcription 3 and extracellular signal regulated 1/2 pathways. rhPCSK6 induces activation of the ERK1/2, STAT3 and NF-kappaB signaling pathways
physiological function
recombinant PCSK6 significantly increases the proliferation, invasion and migraxadtion abilities of breast cancer MDA-MB-231 cells. In addition, PCSK6 treatment reduces cell cycle arrest and prevents apoptosis of MDA-MB-231 cells. PCSK6 treatment also increases the expression of phosphorylated extracellular signal-regulated kinase 1/2 and Wnt family member 3A, suggesting that these pathways are activated by PCSK6. Enzyme PCSK6 may promote the proliferation of breast cancer MDA-MB-231 cells by disturbing cell cycle arrest via the mitogen-activated protein kinase pathway
physiological function
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the enzyme is involved in pro-atrial natriuretic peptide (pro-ANP) processing in the heart, key functions of PCSK6 are in the cardiovascular system to control blood pressure homeostasis
physiological function
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proprotein convertase subtilisin/kexin type 9 negatively regulates the low-density lipoprotein (LDL) receptor in hepatocytes and plays an important role in controlling circulating levels of LDL-cholesterol. It interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor, resulting in results in increased secretion of apoB-containing lipoproteins and increased levels of cholesterol and triacylglycerol. PCSK9/apoB interaction results in increased production of apoB, possibly through the inhibition of intracellular apoB degradation via the autophagosome/lysosome pathway. Role for the enzyme in shuttling between apoB and LDLR-receptor
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additional information
differential structural requirements of the proteolytic site and requirements for secretion in trans in a system that effectively bypasses the need for proteolysis, overview. The enzyme's prodomain inhibits intermolecular proteolysis in trans and requires the C-terminus for full inhibition and proper secretion. the enzyme's active site and its adjacent residues serve as an allosteric modulator of protein secretion independent of its role in proteolysis, specific residues in the protease recognition sequence can differentially modulate the effects on proteolysis and secretion
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
additional information
the enzyme contains a signal peptide and a prodomain followed by a catalytic protease domain, a hinge-region and a C-terminal domain. Areas outside the direct interaction area between PCSK9 and the LDL-R can be targeted to inhibit the PCSK9 triggered degradation of the LDL-receptor, Equilibrium binding parameters for the interaction between the LDL-R ectodomain and wt PCSK9 as well as PCSK9 mutants determined by surface plasmon resonance at 25°C, steady-state analysis and kinetic analysis, overview
additional information
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the enzyme contains a signal peptide and a prodomain followed by a catalytic protease domain, a hinge-region and a C-terminal domain. Areas outside the direct interaction area between PCSK9 and the LDL-R can be targeted to inhibit the PCSK9 triggered degradation of the LDL-receptor, Equilibrium binding parameters for the interaction between the LDL-R ectodomain and wt PCSK9 as well as PCSK9 mutants determined by surface plasmon resonance at 25°C, steady-state analysis and kinetic analysis, overview