PCSK9

This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an autocatalytic processing event with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestine and kidney tissues and escorts specific receptors for lysosomal degradation. It plays a role in cholesterol and fatty acid metabolism. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

Proprotein Convertase Subtilisin/Kexin Type 9

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 (PubMed:18039658).
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 (PubMed:18799458, PubMed:17461796, PubMed:18197702, PubMed:22074827).
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 (PubMed:18660751).
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.

Apoptotic processIEA:UniProtKB-KW
Cellular response to insulin stimulusBy SimilarityISS:HGNC-UCL
Cellular response to starvationBy SimilarityISS:HGNC-UCL
Cholesterol homeostasisManual Assertion Based On ExperimentIMP:HGNC-UCL
Cholesterol metabolic processIEA:UniProtKB-KW
Kidney developmentBy SimilarityISS:HGNC-UCL
Lipoprotein metabolic processIEA:Ensembl
Liver developmentBy SimilarityISS:HGNC-UCL
Low-density lipoprotein particle receptor catabolic processManual Assertion Based On ExperimentIDA:UniProtKB
Lysosomal transportManual Assertion Based On ExperimentIDA:BHF-UCL
Negative regulation of low-density lipoprotein particle clearanceManual Assertion Based On ExperimentIDA:BHF-UCL
Negative regulation of low-density lipoprotein particle receptor bindingManual Assertion Based On ExperimentIDA:BHF-UCL
Negative regulation of low-density lipoprotein receptor activityManual Assertion Based On ExperimentIDA:BHF-UCL
Negative regulation of receptor internalizationManual Assertion Based On ExperimentIDA:ComplexPortal
Negative regulation of receptor recyclingManual Assertion Based On ExperimentIDA:BHF-UCL
Negative regulation of receptor-mediated endocytosis involved in cholesterol transportManual Assertion Based On ExperimentIDA:BHF-UCL
Negative regulation of sodium ion transmembrane transporter activityManual Assertion Based On ExperimentIDA:BHF-UCL
NeurogenesisBy SimilarityISS:HGNC-UCL
Neuron differentiationBy SimilarityISS:HGNC-UCL
Phospholipid metabolic processIEA:Ensembl
Positive regulation of low-density lipoprotein particle receptor catabolic processManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of neuron apoptotic processManual Assertion Based On ExperimentIMP:HGNC-UCL
Positive regulation of receptor internalizationManual Assertion Based On ExperimentIDA:BHF-UCL
Protein autoprocessingManual Assertion Based On ExperimentIDA:HGNC-UCL
Regulation of neuron apoptotic processISS:UniProtKB
Regulation of signaling receptor activityManual Assertion Based On ExperimentIDA:BHF-UCL
Triglyceride metabolic processIEA:Ensembl

Cytoplasm
Secreted
Endosome
Lysosome
Cell surface
Endoplasmic reticulum
Golgi apparatus
Autocatalytic cleavage is required to transport it from the endoplasmic reticulum to the Golgi apparatus and for the secretion of the mature protein. Localizes to the endoplasmic reticulum in the absence of LDLR and colocalizes to the cell surface and to the endosomes/lysosomes in the presence of LDLR. The sorting to the cell surface and endosomes is required in order to fully promote LDLR degradation.

Hypercholesterolemia, familial, 3 (FHCL3):
A form of hypercholesterolemia, a disorder of lipoprotein metabolism characterized by elevated serum low-density lipoprotein (LDL) cholesterol levels, which result in excess deposition of cholesterol in tissues and leads to xanthelasma, xanthomas, accelerated atherosclerosis and increased risk of premature coronary heart disease. FHCL3 inheritance is autosomal dominant.

Cleavage by furin and PCSK5 generates a truncated inactive protein that is unable to induce LDLR degradation.
Undergoes autocatalytic cleavage in the endoplasmic reticulum to release the propeptide from the N-terminus and the cleavage of the propeptide is strictly required for its maturation and activation. The cleaved propeptide however remains associated with the catalytic domain through non-covalent interactions, preventing potential substrates from accessing its active site. As a result, it is secreted from cells as a propeptide-containing, enzymatically inactive protein.
Phosphorylation protects the propeptide against proteolysis.