期刊
DEVELOPMENTAL CELL
卷 21, 期 5, 页码 848-861出版社
CELL PRESS
DOI: 10.1016/j.devcel.2011.09.007
关键词
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资金
- Cancer Research UK
- Wellcome Trust
- UK Medical Research Council
- Spanish Ministry of Science and Innovation [SAF2008-00451, SAF2011-22988]
- Red Tematica de Investigacion Cooperativa en Cancer [RD06/0020/1001]
- Children's Hospital Boston Intellectual and Developmental Disabilities Research Center/National Institute of Child Health and Human Development [P30 HD-18655]
- National Institute of General Medical Sciences [RO1 GM074241]
- Chinese Ministry of Education-University of Oxford
- EMBO
- Medical Research Council [G0700232] Funding Source: researchfish
- MRC [G0700232] Funding Source: UKRI
LDL-receptor-related protein 6 (LRP6), alongside Frizzled receptors, transduces Wnt signaling across the plasma membrane. The LRP6 ectodomain comprises four tandem beta-propeller-EGF-like domain (PE) pairs that harbor binding sites for Wnt morphogens and their antagonists including Dickkopf 1 (Dkkl). 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.
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