Fig. 4

Suppression of LDLR recycling by PCSK9. The LDLR is bound to the cell surface by PCSK9. The LDLR’s epidermal growth factor repeats the catalytic domain of PCSK9 binds A. Through clathrin-mediated endocytosis, the LDLR: PCSK9 complex is taken within the cell. In the sorting endosome, PCSK9 stays attached to the LDLR because of an extra electrostatic contact at acidic pH between the C-terminal domain of PCSK9 and the ligand-binding domain of the LDLR. This prevents the LDLR from achieving a closed conformation, which ultimately leads to degradation rather than recycling. Ectodomain cleavage of the extended LDLR by a cysteine cathepsin in the sorting endosome seems to be the mechanism by which the LDLR fails to recycle. In preparation for destruction in the endosomal/lysosomal tract, the vesicular portion of the sorting endosome will include the cleaved LDLR ectodomain. Consequently, the plasma membrane has a reduced supply of LDLR for the binding and clearance of LDL-C [100, 101]