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Wnt-Frizzled-LRP6 起始复合物的结构揭示了核心受体识别的基础。

Structure of the Wnt-Frizzled-LRP6 initiation complex reveals the basis for coreceptor discrimination.

机构信息

HHMI, Stanford University School of Medicine, Stanford, CA 94305.

Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.

出版信息

Proc Natl Acad Sci U S A. 2023 Mar 14;120(11):e2218238120. doi: 10.1073/pnas.2218238120. Epub 2023 Mar 9.

DOI:10.1073/pnas.2218238120
PMID:36893265
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10089208/
Abstract

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.

摘要

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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bde7/10089208/870f2f9428ed/pnas.2218238120fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bde7/10089208/fbe1cd99b1fd/pnas.2218238120fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bde7/10089208/0c4556e45d08/pnas.2218238120fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bde7/10089208/f304d02250f4/pnas.2218238120fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bde7/10089208/afb19543c891/pnas.2218238120fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bde7/10089208/9f38d82645f1/pnas.2218238120fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bde7/10089208/870f2f9428ed/pnas.2218238120fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bde7/10089208/fbe1cd99b1fd/pnas.2218238120fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bde7/10089208/0c4556e45d08/pnas.2218238120fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bde7/10089208/f304d02250f4/pnas.2218238120fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bde7/10089208/afb19543c891/pnas.2218238120fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bde7/10089208/9f38d82645f1/pnas.2218238120fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bde7/10089208/870f2f9428ed/pnas.2218238120fig06.jpg

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本文引用的文献

[1]
Directed evolution identifies high-affinity cystine-knot peptide agonists and antagonists of Wnt/β-catenin signaling.

Proc Natl Acad Sci U S A. 2022-11-16

[2]
Facile discovery of surrogate cytokine agonists.

Cell. 2022-4-14

[3]
The Wnt Pathway: From Signaling Mechanisms to Synthetic Modulators.

Annu Rev Biochem. 2022-6-21

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DeepEMhancer: a deep learning solution for cryo-EM volume post-processing.

Commun Biol. 2021-7-15

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Highly accurate protein structure prediction with AlphaFold.

Nature. 2021-8

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LRP5 and LRP6 in Wnt Signaling: Similarity and Divergence.

Front Cell Dev Biol. 2021-5-6

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The Genetic Architecture of High Bone Mass.

Front Endocrinol (Lausanne). 2020

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Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains.

Nat Commun. 2020-10-23

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Rapid and robust antibody Fab fragment crystallization utilizing edge-to-edge beta-sheet packing.

PLoS One. 2020-9-11

[10]
Next-Generation Surrogate Wnts Support Organoid Growth and Deconvolute Frizzled Pleiotropy In Vivo.

Cell Stem Cell. 2020-11-5

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