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人卷曲蛋白 5 的结构通过基准辅助 cryo-EM 支持经典 Wnt 信号的异二聚体机制。

Structure of human Frizzled5 by fiducial-assisted cryo-EM supports a heterodimeric mechanism of canonical Wnt signaling.

机构信息

Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United States.

Department of Structural Biology, Stanford University School of Medicine, Stanford, United States.

出版信息

Elife. 2020 Aug 7;9:e58464. doi: 10.7554/eLife.58464.

DOI:10.7554/eLife.58464
PMID:32762848
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7442489/
Abstract

Frizzleds (Fzd) are the primary receptors for Wnt morphogens, which are essential regulators of stem cell biology, yet the structural basis of Wnt signaling through Fzd remains poorly understood. Here we report the structure of an unliganded human Fzd5 determined by single-particle cryo-EM at 3.7 Å resolution, with the aid of an antibody chaperone acting as a fiducial marker. We also analyzed the topology of low-resolution XWnt8/Fzd5 complex particles, which revealed extreme flexibility between the Wnt/Fzd-CRD and the Fzd-TM regions. Analysis of Wnt/β-catenin signaling in response to Wnt3a versus a 'surrogate agonist' that cross-links Fzd to LRP6, revealed identical structure-activity relationships. Thus, canonical Wnt/β-catenin signaling appears to be principally reliant on ligand-induced Fzd/LRP6 heterodimerization, versus the allosteric mechanisms seen in structurally analogous class A G protein-coupled receptors, and Smoothened. These findings deepen our mechanistic understanding of Wnt signal transduction, and have implications for harnessing Wnt agonism in regenerative medicine.

摘要

卷曲蛋白（Fzd）是 Wnt 形态发生素的主要受体，Wnt 形态发生素是干细胞生物学的重要调节剂，但 Fzd 介导 Wnt 信号的结构基础仍知之甚少。在这里，我们报道了在单颗粒冷冻电镜下以 3.7 Å 的分辨率确定的未结合的人 Fzd5 结构，该结构得到了作为基准标记的抗体伴侣的帮助。我们还分析了低分辨率 XWnt8/Fzd5 复合物颗粒的拓扑结构，结果显示 Wnt/Fzd-CRD 和 Fzd-TM 区域之间存在极端的灵活性。对 Wnt3a 与“替代激动剂”（该激动剂交联 Fzd 与 LRP6）引发的 Wnt/β-连环蛋白信号的分析表明，相同的结构-活性关系。因此，经典的 Wnt/β-连环蛋白信号似乎主要依赖于配体诱导的 Fzd/LRP6 异二聚化，而不是在结构类似的 A 类 G 蛋白偶联受体和 Smoothened 中看到的变构机制。这些发现加深了我们对 Wnt 信号转导的机制理解，并对再生医学中利用 Wnt 激动剂具有重要意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/80bdc6c0c4f0/elife-58464-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/a2b6fcc86fc3/elife-58464-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/94f6cceccb04/elife-58464-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/83377269e336/elife-58464-fig1-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/9d93398ebff3/elife-58464-fig1-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/466d84355419/elife-58464-fig1-figsupp4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/a2adf9500644/elife-58464-fig1-figsupp5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/30034ec15fb4/elife-58464-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/7be5eecb8f5d/elife-58464-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/fe1bf35b1647/elife-58464-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/80bdc6c0c4f0/elife-58464-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/a2b6fcc86fc3/elife-58464-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/94f6cceccb04/elife-58464-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/83377269e336/elife-58464-fig1-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/9d93398ebff3/elife-58464-fig1-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/466d84355419/elife-58464-fig1-figsupp4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/a2adf9500644/elife-58464-fig1-figsupp5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/30034ec15fb4/elife-58464-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/7be5eecb8f5d/elife-58464-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/fe1bf35b1647/elife-58464-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/731a/7442489/80bdc6c0c4f0/elife-58464-fig4.jpg

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