Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation.

Frizzled Receptors / metabolism Wnt Signaling Pathway Dishevelled Proteins / metabolism Humans HEK293 Cells Protein Binding Cryoelectron Microscopy Models, Molecular Protein Domains

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
02 Sep 2024

Historique:

received: 24 02 2024

accepted: 28 08 2024

medline: 3 9 2024

pubmed: 3 9 2024

entrez: 2 9 2024

Statut: epublish

Résumé

WNT signaling is fundamental in development and homeostasis, but how the Frizzled receptors (FZDs) propagate signaling remains enigmatic. Here, we present the cryo-EM structure of FZD4 engaged with the DEP domain of Dishevelled 2 (DVL2), a key WNT transducer. We uncover a distinct binding mode where the DEP finger-loop inserts into the FZD4 cavity to form a hydrophobic interface. FZD4 intracellular loop 2 (ICL2) additionally anchors the complex through polar contacts. Mutagenesis validates the structural observations. The DEP interface is highly conserved in FZDs, indicating a universal mechanism by which FZDs engage with DVLs. We further reveal that DEP mimics G-protein/β-arrestin/GRK to recognize an active conformation of receptor, expanding current GPCR engagement models. Finally, we identify a distinct FZD4 dimerization interface. Our findings delineate the molecular determinants governing FZD/DVL assembly and propagation of WNT signaling, providing long-sought answers underlying WNT signal transduction.

Identifiants

DOI: 10.1038/s41467-024-52174-z PMID: 39223191

pubmed: 39223191

doi: 10.1038/s41467-024-52174-z

pii: 10.1038/s41467-024-52174-z

doi:

Substances chimiques

Frizzled Receptors 0

Dishevelled Proteins 0

FZD4 protein, human 0

DVL2 protein, human 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

7644

Subventions

Organisme : National Natural Science Foundation of China (National Science Foundation of China)

ID : 32070048

Informations de copyright

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