title: Molecular basis for LDL receptor recognition by PCSK9.
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.
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050, USA.
authors.forename: Hyock Joo
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Lagace
authors.forename: Markey C
authors.initials: MC
authors.lastname: McNutt
authors.forename: Jay D
authors.initials: JD
authors.lastname: Horton
authors.forename: Johann
authors.initials: J
authors.lastname: Deisenhofer
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008077:Lipoproteins, LDL / Q000097:blood; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011485:Protein Binding; D011487:Protein Conformation; D011973:Receptors, LDL / Q000737:chemistry / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D004815:Epidermal Growth Factor; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases