Like other proprotein convertases (PCs), PCSK9 undergoes an autocatalytic cleavage of its inhibitory prodomain in the endoplasmic reticulum (ER). This results in a heterodimer of the prosegment and the rest of the mature protein, that is proteolytically inactive and allows the protein to exit the ER, traffic though the Golgi apparatus, and become secreted. However, PCSK9 is different from all other PCs that lose their prodomain following a second cleavage or dissociation along their intracellular route before reaching their final destinations, rather, PCSK9 always remains in a tight enzymatically inactive complex with its prodomain.
PCSK9 modulates the level of plasma low density lipoproteins (“LDL”) cholesterol by binding to the LDL receptor (“LDLR”), the principal protein responsible for the elimination of circulating LDL in blood. Following endocytosis of the cell surface PCSK9-LDLR complex into clathrin-coated endosomes, PCSK9 targets the LDLR towards an intracellular degradation compartment. Hence, inhibition of the cell-surface interaction between LDLR and PCSK9, prevents PCSK9-induced LDLR intracellular degradation and thereby enables recirculation of LDLR to the cell surface. As a consequence, inhibition of PCSK9 results in increased cell surface expression of LDLR, uptake of LDL-cholesterol (LDLc) from circulation and, thereby, reduction of plasma cholesterol.