Protein convertase subtilisin/kexin 9 (PCSK9) possesses a signal peptide ( aa 1-30), a prosegment (PRO) (aa 31-152), a catalytic domain (aa 153-407), a hinge region (aa 408-452), and a C-terminal Cys-His-rich domain (CHRD) (aa 453-692).? This protein is primarily synthesized and secreted by hepatocytes.? Besides liver, it is also expressed in the small intestine, kidney, and brain, and it is present in plasma.? Upon translocation to the endoplasmic reticulum, the prosegment of PCSK9 is autocatalytically cleaved at the VFAQ152QSIP site and secreted as a stable, enzymatically inactive, non-covalent complex.? Elevated low density lipoprotein-cholesterol (LDLc) level is a major risk factor for cardiovascular disease and atherosclerosis.? LDLc is cleared from circulation by the LDL receptor (LDLR); PCSK9 is a regulator of LDLc levels through the binding of LDLR, subsequently leading to the degradation of LDLR.? Therefore, it is biologically plausible that drugs inhibiting PCSK9 would lower heart attacks and other diseases caused by increased cholesterol.? PCSK9 also binds to other LDLR family members such as very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER), and apolipoprotein receptor 2 (LRP8/APOER2), which lead to their degradation in the intracellular acidic compartments.? Like the LDLR, gene expression of PCSK9 is positively regulated by SREBP-2, a transcription factor that is activated in response to cellular cholesterol depletion.