Structural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling.
Structural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling.
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DOI：
10.1016/j.devcel.2011.09.007
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发表时间：
2011-11-15
影响因子：
11.8
通讯作者：
Jones, E. Yvonne
中科院分区：
文献类型：
--
作者：
Chen, Shuo;Bubeck, Doryen;MacDonald, Bryan T.;Liang, Wen-Xue;Mao, Jian-Hua;Malinauskas, Tomas;Llorca, Oscar;Aricescu, A. Radu;Siebold, Christian;He, Xi;Jones, E. Yvonne
LDL受体相关蛋白6（LRP 6）与Frizzled受体一起跨质膜转导Wnt信号。LRP 6胞外域包含四个串联的β-螺旋桨-EGF样结构域（PE）对，其具有Wnt形态发生剂及其拮抗剂（包括Dickkopf 1（Dkk 1））的结合位点。为了了解这些多重相互作用是如何整合的，我们将第三和第四对PE的晶体学分析与电子显微镜（EM）相结合，以确定完整的胞外域结构。一个广泛的对间接口，保守的第一至第二和第三至第四PE相互作用，有助于一个紧凑的平台样架构，这是破坏涉及发育性疾病的突变。与分子伴侣Mesd结合的LRP 6平台的EM重建证实了跨越PE对的结合模式。细胞和结合试验确定重叠的Wnt 3a-和Dkk 1-结合表面上的第三个PE对，符合空间竞争，但也提出了一个模型，其中的平台结构支持通过多个相互作用位点的配体的相互作用。
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.
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