title: Structural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling.
abstract: LDL-receptor-related protein 6 (LRP6), alongside Frizzled receptors, transduces Wnt signaling across the plasma membrane. The LRP6 ectodomain comprises four tandem β-propeller-EGF-like domain (PE) pairs that harbor binding sites for Wnt morphogens and their antagonists including Dickkopf 1 (Dkk1). To understand how these multiple interactions are integrated, we combined crystallographic analysis of the third and fourth PE pairs with electron microscopy (EM) to determine the complete ectodomain structure. An extensive inter-pair interface, conserved for the first-to-second and third-to-fourth PE interactions, contributes to a compact platform-like architecture, which is disrupted by mutations implicated in developmental diseases. EM reconstruction of the LRP6 platform bound to chaperone Mesd exemplifies a binding mode spanning PE pairs. Cellular and binding assays identify overlapping Wnt3a- and Dkk1-binding surfaces on the third PE pair, consistent with steric competition, but also suggest a model in which the platform structure supports an interplay of ligands through multiple interaction sites.
authors: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. shuo@strubi.ox.ac.uk
authors: Shuo
authors: S
authors: Chen
authors: Doryen
authors: D
authors: Bubeck
authors: Bryan T
authors: BT
authors: MacDonald
authors: Wen-Xue
authors: WX
authors: Liang
authors: Jian-Hua
authors: JH
authors: Mao
authors: Tomas
authors: T
authors: Malinauskas
authors: Oscar
authors: O
authors: Llorca
authors: A Radu
authors: AR
authors: Aricescu
authors: Christian
authors: C
authors: Siebold
authors: Xi
authors: X
authors: He
authors: E Yvonne
authors: EY
authors: Jones
mesh_terms: D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051153:Wnt Proteins