PCSK9 function and physiology

Abstract

PCSK9 has exploded onto center stage plasma cholesterol metabolism, raising hopes for a new strategy to treat hypercholesterolemia. PCSK9 in a plasma protein that triggers increased degradation of the LDL receptor. Gain-of-function mutations in PCSK9 reduce LDL receptor levels in the liver, resulting in high levels of LDL cholesterol in the plasma and increased susceptibility to coronary heart disease. Loss-of-function mutations lead to higher levels of the LDL receptor, lower LDL cholesterol levels and protection from coronary heart disease. Two papers in this issue of the Journal of Lipid Research exemplify the rapid pace of progress in understanding PCSK9 molecular interactions and physiology. Dr. Shilpa Pandit and coworkers from Merck Research Laboratories describe the functional basis for the hypercholesterolemia associated with gain-of-function missense mutations in PCSK9. Dr. Jay Horton's group at UT Southwestern describe the kinetics and metabolism of PCSK9 and the impact of PCSK9 on LDL receptors in the liver and adrenal gland.

Fig. 1

A: Model of PCSK9-mediated sorting of LDL receptors to lysosomes. The EGFa domain of the LDL receptor is required for proper sorting of the LDL receptor back to the cell surface (–32). The EGFa domain may contain a sorting signal that interacts with an endosomal protein (green star), directing the LDL receptor back to the cell surface on recycling endosomes (green arrows). Binding of PCSK9 might interfere with that signal, preventing the LDL receptor from returning to the cell surface. Alternatively, PCSK9 could contain a distinct sorting signal (red star) that results in the sorting of the PCSK9–LDL receptor complex (red arrows) to lysosomes. The gain-of-function mutation involving S127 of PCSK9 may enhance the sorting of the PCSK9–LDL receptor complex to lysosomes (12). B: The structure of the LDL receptor and PCSK9 at endosomal pH. The LDL receptor is folded back upon itself at low pH (31); however, the face of the EGFa domain that binds PCSK9 (31) is exposed. The LDL receptor–binding site on PCSK9 is at the apex of a roughly triangular structure formed by the tripartite domain structure of PCSK9 (26). The D374 residue that is altered in gain-of-function PCSK mutants is located within the apical LDL receptor–binding site, whereas the S127 residue is quite distant from the binding interface. S127 mutations do not affect binding of PCSK9 to the LDL receptor (12). Gain-of-function mutations affecting residue 127 may reduce LDL receptors by enhancing the sorting of LDL receptors to lysosomes, rather than by affecting the strength of PCSK9–LDL receptor interactions (12).