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Structural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling.

DOI: 10.1016/j.devcel.2011.09.007 DOI Help
PMID: 3564486 PMID Help

Authors: Shuo Chen (University of Oxford) , Doryen Bubeck (University of Oxford) , Bryan T Macdonald (Harvard Medical School, Boston, USA.) , Wen-xue Liang (Shanghai Jiao Tong University School of Medicine, China) , Jian-hua Mao (Shanghai Jiao Tong University School of Medicine, China) , Tomas Malinauskas (University of Oxford) , Oscar Llorca (Centro de Investigaciones Biológicas (CIB), Madrid, Spain) , Alexandru Aricescu (Division of Structural Biology, University of Oxford) , Christian Siebold (Wellcome Trust Centre for Human Genetics, University of Oxford) , Xi He (Harvard Medical School, Boston, USA.) , Edith Jones (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Developmental Cell , VOL 21 , PAGES 848 - 861

State: Published (Approved)
Published: December 2011

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 which 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.

Journal Keywords: X-Ray; HEK293; Humans; Low; Models; Molecular; Protein; Tertiary; Wnt; Wnt Signaling Pathway

Subject Areas: Biology and Bio-materials

Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 04/04/2012 12:08

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