PCSK9: Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways. Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3). A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins. Belongs to the peptidase S8 family. 2 isoforms of the human protein are produced by alternative splicing.
Protein type: Secreted; EC 3.4.21.-; Secreted, signal peptide; Cell development/differentiation; Protease
Cellular Component: cell surface; cytoplasm; early endosome; endoplasmic reticulum; endosome; ER to Golgi transport vesicle; extracellular region; extracellular space; Golgi apparatus; late endosome; lysosome; perinuclear region of cytoplasm; plasma membrane; rough endoplasmic reticulum
Molecular Function: apolipoprotein binding; apolipoprotein receptor binding; hydrolase activity; low-density lipoprotein binding; low-density lipoprotein receptor binding; peptidase activity; protein self-association; receptor inhibitor activity; serine-type endopeptidase activity; serine-type peptidase activity; sodium channel inhibitor activity; very-low-density lipoprotein binding
Biological Process: apoptosis; cellular response to insulin stimulus; cellular response to starvation; cholesterol homeostasis; cholesterol metabolic process; lipid metabolic process; lipoprotein metabolic process; low-density lipoprotein receptor catabolic process; low-density lipoprotein receptor metabolic process; lysosomal transport; negative regulation of receptor recycling; neuron differentiation; phospholipid metabolic process; positive regulation of low-density lipoprotein receptor catabolic process; positive regulation of neuron apoptosis; positive regulation of receptor internalization; protein autoprocessing; protein processing; proteolysis; regulation of low-density lipoprotein receptor catabolic process; regulation of neuron apoptosis; regulation of receptor activity; steroid metabolic process; triacylglycerol metabolic process
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