Structure of human Frizzled5 by fiducial-assisted cryo-EM supports a heterodimeric mechanism of canonical Wnt signaling.
Cryo-EM
Frizzled
Wnt
canonical Wnt/β-catenin signaling
human
molecular biophysics
structural biology
surrogate Wnt agonist
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
07 08 2020
07 08 2020
Historique:
received:
01
05
2020
accepted:
06
08
2020
pubmed:
9
8
2020
medline:
12
2
2021
entrez:
9
8
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32762848
doi: 10.7554/eLife.58464
pii: 58464
pmc: PMC7442489
doi:
pii:
Substances chimiques
FZD5 protein, human
0
Frizzled Receptors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK115728
Pays : United States
Organisme : NIGMS NIH HHS
ID : P50 GM082545
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM117372
Pays : United States
Organisme : Human Frontier Science Program
ID : LT000011/2016-L
Pays : International
Organisme : NIH HHS
ID : 1R01DK115728
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI125320
Pays : United States
Organisme : U.S. Department of Energy
ID : DE-AC02-76SF00515
Pays : International
Informations de copyright
© 2020, Tsutsumi et al.
Déclaration de conflit d'intérêts
NT, SM, DW, KJ, YM, JB, NA, AK, CG No competing interests declared, CJ, KG KCG and CYJ are founders of Surrozen Therapeutics.
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