Molecular basis for LDL receptor recognition by PCSK9

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-...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2008-02, Vol.105 (6), p.1820-1825
Main Authors: Kwon, Hyock Joo, Lagace, Thomas A, McNutt, Markey C, Horton, Jay D, Deisenhofer, Johann
Format: Article
Language:English
Subjects:
Autocatalysis
Binding Sites
Biochemistry
Biological Sciences
Calcium
Cell Line
Cells
Crystal structure
Epidermal Growth Factor - chemistry
Epidermal Growth Factor - metabolism
Humans
Hydrogen-Ion Concentration
LDL receptors
Ligands
Lipoproteins, LDL - blood
Models, Molecular
Molecules
Mutagenesis, Site-Directed
Mutation
Oxygen
Proprotein Convertase 9
Proprotein Convertases
Protein Binding
Protein Conformation
Proteins
Receptors
Receptors, LDL - chemistry
Receptors, LDL - metabolism
Salts
Serine Endopeptidases - chemistry
Serine Endopeptidases - genetics
Serine Endopeptidases - metabolism
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0712064105