title: Structural basis of Wnt signaling inhibition by Dickkopf binding to LRP5/6.
abstract: LDL receptor-related proteins 5 and 6 (LRP5/6) are coreceptors for Wnt growth factors, and also bind Dkk proteins, secreted inhibitors of Wnt signaling. The LRP5/6 ectodomain contains four β-propeller/EGF-like domain repeats. The first two repeats, LRP6(1-2), bind to several Wnt variants, whereas LRP6(3-4) binds other Wnts. We present the crystal structure of the Dkk1 C-terminal domain bound to LRP6(3-4), and show that the Dkk1 N-terminal domain binds to LRP6(1-2), demonstrating that a single Dkk1 molecule can bind to both portions of the LRP6 ectodomain and thereby inhibit different Wnts. Small-angle X-ray scattering analysis of LRP6(1-4) bound to a noninhibitory antibody fragment or to full-length Dkk1 shows that in both cases the ectodomain adopts a curved conformation that places the first three repeats at a similar height relative to the membrane. Thus, Wnts bound to either portion of the LRP6 ectodomain likely bear a similar spatial relationship to Frizzled coreceptors.
authors: Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Victoria E
authors: VE
authors: Ahn
authors: Matthew Ling-Hon
authors: ML
authors: Chu
authors: Hee-Jung
authors: HJ
authors: Choi
authors: Denise
authors: D
authors: Tran
authors: Arie
authors: A
authors: Abo
authors: William I
authors: WI
authors: Weis
mesh_terms: D001665:Binding Sites; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000737:chemistry / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D011487:Protein Conformation; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C555482:LRP5 protein, human; C555475:LRP6 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051153:Wnt Proteins