PCSK9
Encyclopedia
Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is an enzyme
which in humans is encoded by the PCSK9 gene
with orthologs found across many species.
subfamily of the secretory subtilase family. The encoded protein is synthesized as a soluble zymogen
that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum
. The protein may function as a proprotein convertase.
This protein plays a major regulatory role in cholesterol
homeostasis. PCSK9 binds to the epidermal growth factor-like repeat A (EGF-A) domain of the low-density lipoprotein receptor (LDLR), inducing LDLR degradation. Reduced LDLR levels result in decreased metabolism of low-density lipoproteins, which could lead to hypercholesterolemia.
PCSK9 may also have a role in the differentiation of cortical neurons.
(HCHOLA3).
The mutations appear to cause the disease by increasing its protease activity, reducing LDL receptor levels and thereby preventing the uptake of cholesterol into the cells.
Several variants of PCSK9 have also been shown to significantly reduce circulating cholesterol. Some variants, which only reduce cholesterol by 15% in whites, has been shown to produce a concurrent reduction in coronary heart disease by 50%, which has major implications for public health.
Inhibition of PCSK9 function is currently being explored as a means of lowering cholesterol levels.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
which in humans is encoded by the PCSK9 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
with orthologs found across many species.
Function
This gene encodes a proprotein convertase belonging to the proteinase KProteinase K
Proteinase K is a broad-spectrum serine protease. The enzyme was discovered in 1974 in extracts of the fungus Engyodontium album . Proteinase K is able to digest native keratin , hence, the name "Proteinase K"...
subfamily of the secretory subtilase family. The encoded protein is synthesized as a soluble zymogen
Zymogen
A zymogen is an inactive enzyme precursor. A zymogen requires a biochemical change for it to become an active enzyme. The biochemical change usually occurs in a lysosome where a specific part of the precursor enzyme is cleaved in order to activate it...
that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
. The protein may function as a proprotein convertase.
This protein plays a major regulatory role in cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
homeostasis. PCSK9 binds to the epidermal growth factor-like repeat A (EGF-A) domain of the low-density lipoprotein receptor (LDLR), inducing LDLR degradation. Reduced LDLR levels result in decreased metabolism of low-density lipoproteins, which could lead to hypercholesterolemia.
PCSK9 may also have a role in the differentiation of cortical neurons.
Clinical significance
Mutations in this gene have been associated with a rare form of autosomal dominant familial hypercholesterolemiaFamilial hypercholesterolemia
Familial hypercholesterolemia is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein , in the blood and early cardiovascular disease...
(HCHOLA3).
The mutations appear to cause the disease by increasing its protease activity, reducing LDL receptor levels and thereby preventing the uptake of cholesterol into the cells.
Several variants of PCSK9 have also been shown to significantly reduce circulating cholesterol. Some variants, which only reduce cholesterol by 15% in whites, has been shown to produce a concurrent reduction in coronary heart disease by 50%, which has major implications for public health.
Inhibition of PCSK9 function is currently being explored as a means of lowering cholesterol levels.