HHMI, Stanford University School of Medicine, Stanford, CA 94305.
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2023 Mar 14;120(11):e2218238120. doi: 10.1073/pnas.2218238120. Epub 2023 Mar 9.
Wnt morphogens are critical for embryonic development and tissue regeneration. Canonical Wnts form ternary receptor complexes composed of tissue-specific Frizzled (Fzd) receptors together with the shared LRP5/6 coreceptors to initiate β-catenin signaling. The cryo-EM structure of a ternary initiation complex of an affinity-matured XWnt8-Frizzled8-LRP6 complex elucidates the basis of coreceptor discrimination by canonical Wnts by means of their N termini and linker domains that engage the LRP6 E1E2 domain funnels. Chimeric Wnts bearing modular linker "grafts" were able to transfer LRP6 domain specificity between different Wnts and enable non-canonical Wnt5a to signal through the canonical pathway. Synthetic peptides comprising the linker domain serve as Wnt-specific antagonists. The structure of the ternary complex provides a topological blueprint for the orientation and proximity of Frizzled and LRP6 within the Wnt cell surface signalosome.
Wnt 形态发生素对于胚胎发育和组织再生至关重要。经典 Wnt 形成由组织特异性卷曲受体（Frizzled，Fzd）与共享的 LRP5/6 核心受体组成的三元受体复合物，以启动 β-连环蛋白信号。通过其 N 末端和连接子结构域与 LRP6 E1E2 结构域漏斗结合，阐明了亲和力成熟的 XWnt8-Frizzled8-LRP6 三元起始复合物的冷冻电镜结构，揭示了经典 Wnt 通过其 N 末端和连接子结构域识别核心受体的基础。携带模块化连接子“移植物”的嵌合 Wnt 能够在不同的 Wnt 之间转移 LRP6 结构域特异性，并使非经典 Wnt5a 通过经典途径发出信号。包含连接子结构域的合成肽作为 Wnt 特异性拮抗剂。三元复合物的结构为 Frizzled 和 LRP6 在 Wnt 细胞表面信号转导体中的取向和接近性提供了拓扑蓝图。
