PCSK9: a convertase that coordinates LDL catabolism

Abstract

The identification and characterization of proprotein convertase subtilisin-like/kexin type 9 (PCSK9) have provided new insights into LDL metabolism and the causal role of LDL in coronary heart disease (CHD). PCSK9 is a secreted protease that mediates degradation of the LDL receptor by interacting with the extracellular domain and targeting the receptor for degradation. Individuals with loss-of-function mutations in PCSK9 have reduced plasma levels of LDL cholesterol and are protected from CHD; these observations have validated PCSK9 as a therapeutic target and suggested new approaches for the treatment and prevention of CHD.

Fig. 1.

PCSK9-mediated degradation of the LDLR. A: Schematic of the major domains of PCSK9. The location of the aspartate (D), histidine (H), and serine (S) that comprise the catalytic triad and the site of binding of the single N-linked sugar (N533) are shown. PCSK9 posttranslational modifications include glycosylation (G) (4), phosphorylations (P) at S47 and S688 (5), and sulfation (S) at Y38 and at another undefined tyrosine in the catalytic domain (6). B: Cellular trafficking and potential sites of PCSK9 action. After undergoing autocatalytic cleavage in the ER, the prodomain (purple) remains associated with the catalytic fragment (green) and the complex is secreted into the plasma. Secreted PCSK9 binds to LDLRs on the cell surface, and the LDLR/PCSK9 complex is internalized via the adaptor protein ARH (LDLRAP). PCSK9 may prevent the recycling of LDLRs from endosomes to the cell surface or direct LDLRs to lysosomes for degradation. A second intracellular pathway has been proposed (11) in which PCSK9 binds the LDLR in a post-ER compartment and targets LDLR for degradation in lysosomes. C: Model for full-length LDLR bound to PCSK9. The EGF-A domain of the LDLR (blue) at acidic pH and the PCSK9:EGF-A complex were superimposed. PCSK9 binds on the outside surface of LDLR. SS, signal sequence; Pro, prodomain.

Fig. 2.

Relationship between cumulative LDL-C exposure and age. Cumulative plasma levels of LDL-C were estimated from mean plasma levels of LDL-C for FH homozygotes (46), FH heterozygotes (46), age-adjusted LDL-C levels in normal individuals [calculated from National Health and Nutrition Education Survey III (47, 48)], and PCSK9 heterozygotes (3). The horizontal red line represents a theoretical threshold of the cumulative LDL exposure required for development of CHD. The height of the red line will be lower in the presence of additional CHD risk factors (e.g., male sex, smoking, diabetes, and hypertension).