PCSK9 mutated D374T
Domain
The C-terminal domain (CRD) is essential for the LDLR-binding and degrading activities.
The catalytic domain is responsible for mediating its self-association.
Function
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:17461796, PubMed:18197702, PubMed:18799458, 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.
Involvement in disease
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.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
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.
Sequence Similarities
Belongs to the peptidase S8 family.
Tissue Specificity
Expressed in neuro-epithelioma, colon carcinoma, hepatic and pancreatic cell lines, and in Schwann cells.
Cellular localization
- 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.
Alternative names
NARC1, PSEC0052, PCSK9, Proprotein convertase subtilisin/kexin type 9, Neural apoptosis-regulated convertase 1, Proprotein convertase 9, Subtilisin/kexin-like protease PC9, NARC-1, PC9