6WW2

Structure of human Frizzled5 by fiducial-assisted cryo-EM

6WW2 の概要

• エントリーDOI: 10.2210/pdb6ww2/pdb
• EMDBエントリー: 21927
• 分子名称: anti-BRIL Fab Heavy chain, anti-Fab Nanobody, anti-BRIL Fab Light chain, ... (4 entities in total)
• 機能のキーワード: wnt pathway, frizzled, developmental biology, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 135819.85

構造登録者

Tsutsumi, N.,Jude, K.M.,Gati, C.,Garcia, K.C. (登録日: 2020-05-07, 公開日: 2020-08-19, 最終更新日: 2024-11-06)

主引用文献

Tsutsumi, N.,Mukherjee, S.,Waghray, D.,Janda, C.Y.,Jude, K.M.,Miao, Y.,Burg, J.S.,Aduri, N.G.,Kossiakoff, A.A.,Gati, C.,Garcia, K.C.
Structure of human Frizzled5 by fiducial-assisted cryo-EM supports a heterodimeric mechanism of canonical Wnt signaling.
Elife, 9:-, 2020

PubMed 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.

PubMed: 32762848
DOI: 10.7554/eLife.58464

実験手法

ELECTRON MICROSCOPY (3.7 Å)