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-Structure paper
Title | Structure of the Wnt-Frizzled-LRP6 initiation complex reveals the basis for coreceptor discrimination. |
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Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 120, Issue 11, Page e2218238120, Year 2023 |
Publish date | Mar 14, 2023 |
Authors | Naotaka Tsutsumi / Sunhee Hwang / Deepa Waghray / Simon Hansen / Kevin M Jude / Nan Wang / Yi Miao / Caleb R Glassman / Nathanael A Caveney / Claudia Y Janda / Rami N Hannoush / K Christopher Garcia / |
PubMed 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 ...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. |
External links | Proc Natl Acad Sci U S A / PubMed:36893265 / PubMed Central |
Methods | EM (single particle) / X-ray diffraction |
Resolution | 1.72 - 3.8 Å |
Structure data | EMDB-26989, PDB-8ctg: PDB-8ffe: |
Chemicals | ChemComp-PAM: ChemComp-GOL: ChemComp-NA: ChemComp-SIN: ChemComp-HOH: |
Source |
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Keywords | SIGNALING PROTEIN / signaling complex / beta-catenin / SIGNALING PROTEIN/Immune System / WNT / RECEPTOR / LRP5 / LRP6 / LDL RECEPTOR-LIKE PROTEIN / YWTD B-PROPELLER / SIGNALING PROTEIN-Immune System complex |