Top Highlights

• PCSK9 contains a signal peptide [amino acid (aa) 1-30], a prodomain (Pro) (aa 31-152), a catalytic domain (CAT) (aa 153-425) and a Cys and His-rich C-terminal domain (CTD) (aa 426-692) (13) (Figure 1).
• PCSK9 induces degradation of LDLR and its family members, including very low-density lipoprotein receptor (VLDLR), apolipoprotein E receptor 2 (ApoER2), and LDLR-related protein 1 (LRP1) (10, 18–20), thereby playing an essential role in lipid metabolism. However, PCSK9 at a physiological concentration can effectively degrade LDLR but not other LDLR...
• After endocytosis, PCSK9 remains bound to LDLR in the acidic endosome, preventing LDLR from recycling and redirecting the receptor to the lysosome for degradation
• PCSK9 can also promote LDLR degradation via an intracellular pathway, especially when overexpressed in cultured cell
• Of note, evolocumab and alirocumab are humanized monoclonal anti-PCSK9 antibodies targeting the catalytic domain of PCSK9. They block PCSK9 binding to LDLR on the cell surface and do not affect the intracellular pathway.

Domain