Download MendeleyMolecular basis for LDL receptor recognition by PCSK9.
Kwon, H.J., Lagace, T.A., McNutt, M.C., Horton, J.D., Deisenhofer, J.(2008) Proc Natl Acad Sci U S A 105: 1820-1825
- PubMed: 18250299
- DOI: https://doi.org/10.1073/pnas.0712064105
- Primary Citation of Related Structures:
3BPS - PubMed Abstract:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) posttranslationally regulates hepatic low-density lipoprotein receptors (LDLRs) by binding to LDLRs on the cell surface, leading to their degradation. The binding site of PCSK9 has been localized to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR. Here, we describe the crystal structure of a complex between PCSK9 and the EGF-A domain of the LDLR. The binding site for the LDLR EGF-A domain resides on the surface of PCSK9's subtilisin-like catalytic domain containing Asp-374, a residue for which a gain-of-function mutation (Asp-374-Tyr) increases the affinity of PCSK9 toward LDLR and increases plasma LDL-cholesterol (LDL-C) levels in humans. The binding surface on PCSK9 is distant from its catalytic site, and the EGF-A domain makes no contact with either the C-terminal domain or the prodomain. Point mutations in PCSK9 that altered key residues contributing to EGF-A binding (Arg-194 and Phe-379) greatly diminished binding to the LDLR's extracellular domain. The structure of PCSK9 in complex with the LDLR EGF-A domain defines potential therapeutic target sites for blocking agents that could interfere with this interaction in vivo, thereby increasing LDLR function and reducing plasma LDL-C levels.
Organizational Affiliation:
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050, USA.
