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Cited by 389

The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.

Molecular basis for LDL receptor recognition by PCSK9

Kwon, Hyock Joo, Lagace, Thomas A., McNutt, Markey C., Horton, Jay D., Deisenhofer, Johann·2008·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0712064105
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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.

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Metadata

Authors
Kwon, H. J., Lagace, T. A., McNutt, M. C., Horton, J. D., & Deisenhofer, J.
Affiliations
  • Departments of *Biochemistry,
  • Molecular Genetics, and
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2008-02-12
Volume
105
Issue
6
Pages
1820-1825
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.0712064105
Cited by
389
References
5
Language
en

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