PCSK9

Developmental stage

In the embryo, expressed in the liver at 9 dpc, in the skin and transiently in the telencephalon at 12 dpc, and in the kidney, small intestine and cerebellum at 15 dpc.

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. 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.

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 (By similarity).

Phosphorylation protects the propeptide against proteolysis.

Sequence similarities

Belongs to the peptidase S8 family.

Tissue specificity

Hepatocytes, kidney mesenchymal cells, intestinal ileum, colon epithelia and embryonic brain telencephalon neurons.

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 co-localizes 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 (By similarity).

Alternative names

• Proprotein convertase subtilisin/kexin type 9
• Neural apoptosis-regulated convertase 1
• Proprotein convertase 9
• Subtilisin/kexin-like protease PC9
• NARC-1
• PC9
• Narc1
• Pcsk9

Database links

• entrezGene:100102
• swissprot:Q80W65

Target type

Proteins

Molecular weight

74823Da