title: structural Studies of Wnts and identification of an LRP6 binding site.
abstract: Wnts are secreted growth factors that have critical roles in cell fate determination and stem cell renewal. The Wnt/β-catenin pathway is initiated by binding of a Wnt protein to a Frizzled (Fzd) receptor and a coreceptor, LDL receptor-related protein 5 or 6 (LRP5/6). We report the 2.1 Å resolution crystal structure of a Drosophila WntD fragment encompassing the N-terminal domain and the linker that connects it to the C-terminal domain. Differences in the structures of WntD and Xenopus Wnt8, including the positions of a receptor-binding β hairpin and a large solvent-filled cavity in the helical core, indicate conformational plasticity in the N-terminal domain that may be important for Wnt-Frizzled specificity. Structure-based mutational analysis of mouse Wnt3a shows that the linker between the N- and C-terminal domains is required for LRP6 binding. These findings provide important insights into Wnt function and evolution.
authors.affiliation: Departments of Structural Biology and Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Matthew Ling-Hon
authors.initials: ML
authors.lastname: Chu
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Ahn
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: Choi
authors.forename: Danette L
authors.initials: DL
authors.lastname: Daniels
authors.forename: Roel
authors.initials: R
authors.lastname: Nusse
authors.forename: William I
authors.initials: WI
authors.lastname: Weis
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D029721:Drosophila Proteins / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D006860:Hydrogen Bonding; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000737:chemistry*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D015533:Transcriptional Activation; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; C504611:WntD protein, Drosophila