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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.

Original publication

DOI

10.1016/j.devcel.2011.09.007

Type

Journal article

Journal

Dev Cell

Publication Date

15/11/2011

Volume

21

Pages

848 - 861

Keywords

Crystallography, X-Ray, HEK293 Cells, Humans, Low Density Lipoprotein Receptor-Related Protein-6, Models, Molecular, Protein Structure, Tertiary, Wnt Proteins, Wnt Signaling Pathway