Molecular biology of PCSK9: its role in LDL metabolism

Abstract

Proprotein convertase subtilisin-like kexin type 9 (PCSK9) is a newly discovered serine protease that destroys low density lipoprotein (LDL) receptors in liver and thereby controls the level of LDL in plasma. Mutations that increase PCSK9 activity cause hypercholesterolemia and coronary heart disease (CHD); mutations that inactivate PCSK9 have the opposite effect, lowering LDL levels and reducing CHD. Although the mechanism of PCSK9 action is not yet clear, the protease provides a new therapeutic target to lower plasma levels of LDL and prevent CHD.

Figure 1

A schematic of PCSK9 with the location of naturally occurring mutations associated with elevated (top) or reduced (bottom) plasma levels of LDL-C. The major domains of PCSK9 are delineated using different colors. The mutations included are limited to those associated with significant differences in plasma levels of LDL-C in at least two independent populations or those that co-segregate consistently with hypercholesterolemia in families. Mutations associated with elevated plasma cholesterol levels found only in families who also have mutations in the LDLR are indicated by with an asterisk (*) [18]. The mutations for which there is functional information are referenced in Table 1. The location of the aspartic acid (D), histidine (H) and serine (S) comprising the catalytic triad and the site of binding of the single N-linked sugar (Asn533) are shown [1]. The oxyanion hole is located at Asn317. Abbreviations: SS, signal sequence; Pro, prodomain.

Figure 2

Cellular trafficking and potential sites of PCSK9 action. PCSK9 undergoes autocatalytic cleavage in the ER. The cleaved prodomain (light blue) associates with the catalytic fragment (dark blue) and functions as a chaperone permitting the mature protein to move from the ER into the secretory pathway. Current evidence indicates that PCSK9 might work at two cellular sites. The first potential location is in a post-ER compartment, depicted here as the Golgi apparatus, where PCSK9 might target the LDLRs (green) for degradation in an acidic compartment such as the lysosome. In the second possible pathway, the PCSK9 that is secreted binds to LDLRs on the cell surface. The LDLR–PCSK9 complex is internalized together with the adaptor protein ARH (orange). PCSK9 might prevent the recycling of the LDLR from the endosome back to the cell surface and/or direct the LDLR to the lysosome where it is degraded. It is currently not known whether PCSK9 directly cleaves the LDLR or whether catalytic activity is required for either pathway.