Structure of the Wnt-Frizzled-LRP6 initiation complex reveals the basis for coreceptor discrimination.
Wnt signaling
cryo-EM
crystallography
protein engineering
structural biology
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
14 03 2023
14 03 2023
Historique:
entrez:
9
3
2023
pubmed:
10
3
2023
medline:
14
3
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36893265
doi: 10.1073/pnas.2218238120
pmc: PMC10089208
doi:
Substances chimiques
Wnt Proteins
0
Low Density Lipoprotein Receptor-Related Protein-6
0
Frizzled Receptors
0
beta Catenin
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
Pagination
e2218238120Subventions
Organisme : NIGMS NIH HHS
ID : P30 GM124169
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM133894
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK115728
Pays : United States
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