Proprotein Convertase Subtilisin/Kexin Type 9: From the Discovery to the Development of New Therapies for Cardiovascular Diseases
Figure 1
Schematic representation of the PCSK9-mediated LDLR degradation process. (a) On the cell surface at neutral pH, the LDLR can adopt an open extended conformation and binds to LDL predominantly through the L4 and L5 domains of the LDL repeats. At low endosomal pH, LDLR adopts the closed form releasing the LDL and allowing its recycle to the cell surface. (b) Circulating PCSK9 binds the LDLR, restraining its flexibility at the EFG-B-propeller interface. The low pH of the endosomes enhances PCSK9/LDLR affinity, preventing complex dissociation and conformational changes leading to lysosomal LDLR degradation. A possible interaction of the PCSK9 C-terminal domain (CTD) at the endosomal pH has also been described to strengthen the binding between the two proteins.
