Structure of the Wnt-Frizzled-LRP6 initiation complex reveals the basis for coreceptor discrimination.
Structure of the Wnt-Frizzled-LRP6 initiation complex reveals the basis for coreceptor discrimination.
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Wnt-Frizzled-LRP6启动络合物的结构揭示了受体歧视的基础。
DOI：
10.1073/pnas.2218238120
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发表时间：
2023-03-14
影响因子：
11.1
通讯作者：
Garcia, K. Christopher
中科院分区：
文献类型：
--
作者：
Tsutsumi, Naotaka;Hwang, Sunhee;Waghray, Deepa;Hansen, Simon;Jude, Kevin M.;Wang, Nan;Miao, Yi;Glassman, Caleb R.;Caveney, Nathanael A.;Janda, Claudia Y.;Hannoush, Rami N.;Garcia, K. Christopher
Wnt - frizzled - lrp6复合体的结构揭示了启动典型Wnt/β-catenin信号传导的基础。Wnt通过两个灵活的Wnt环与LRP6结合的不寻常的“串联锚定”模式阐明了典型Wnt信号复合物的自然拓扑结构，可以作为设计“替代”Wnt的结构蓝图，以模仿内源性Wnt诱导的二聚化模式。将这些环嫁接到不同的wnt上，改变了它们对LRP6细胞外结构域的结合选择性。LRP6的Wnt与“非规范”共受体区分的模块化特性，开启了交换连接域以创建具有改变再生医学和癌症生物学功能的“设计Wnt”的可能性。Wnt形成因子对胚胎发育和组织再生至关重要。典型wnt形成由组织特异性卷曲（Fzd）受体与共享的LRP5/6辅受体组成的三元受体复合物，启动β-catenin信号传导。亲和成熟的XWnt8-Frizzled8-LRP6复合物的三元起始复合物的低温电镜结构阐明了典型wnt通过其N端和连接域参与LRP6 E1E2结构域通道的辅助受体识别的基础。嵌合Wnts承载模块化接头“移植物”能够在不同的Wnts之间转移LRP6结构域特异性，并使非规范Wnt5a通过规范途径发出信号。包含连接域的合成肽作为wnt特异性拮抗剂。三元配合物的结构为Wnt细胞表面信号体中Frizzled和LRP6的取向和邻近性提供了拓扑蓝图。
The structure of the signaling-competent Wnt–Frizzled–LRP6 complex reveals the basis for initiating canonical Wnt/β-catenin signaling. An unusual “tandem anchoring” mode for Wnt binding to LRP6 via two flexible loops of Wnt clarifies the natural topology of the canonical Wnt signaling complex that could serve as a structural blueprint for designing “surrogate” Wnts to mimic the endogenous Wnt-induced dimerization mode. Grafting these loops onto different Wnts changes their binding selectivity for LRP6 extracellular domains. The modular nature of Wnt discrimination of LRP6 from the “non-canonical” coreceptors opens the possibility of swapping the linker domain to create “designer Wnts” with altered functions in regenerative medicine and cancer biology. 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.
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影响因子：
64.8
作者：
Glinka, A;Wu, W;Niehrs, C
通讯作者：
Niehrs, C
影响因子：
4.8
作者：
Bourhis, Eric;Tam, Christine;Hannoush, Rami N.
通讯作者：
Hannoush, Rami N.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
7.7
作者：
Cho, Chris;Wang, Yanshu;Nathans, Jeremy
通讯作者：
Nathans, Jeremy
影响因子：
48
作者：
Bepler, Tristan;Morin, Andrew;Berger, Bonnie
通讯作者：
Berger, Bonnie