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TitleStructure of the Wnt-Frizzled-LRP6 initiation complex reveals the basis for coreceptor discrimination.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 120, Issue 11, Page e2218238120, Year 2023
Publish dateMar 14, 2023
AuthorsNaotaka 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 AbstractWnt 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 linksProc Natl Acad Sci U S A / PubMed:36893265 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.72 - 3.8 Å
Structure data

26989

8ctg

EMDB-26989, PDB-8ctg:
Extracellular architecture of an engineered canonical Wnt signaling ternary complex
Method: EM (single particle) / Resolution: 3.8 Å

PDB-8ffe:
Crystal structure of LRP6 E1E2 domains bound to YW210.09 Fab and engineered XWnt8 peptide
Method: X-RAY DIFFRACTION / Resolution: 1.72 Å

Chemicals

ChemComp-PAM:
PALMITOLEIC ACID / Palmitoleic acid

ChemComp-GOL:
GLYCEROL / Glycerol

ChemComp-NA:
Unknown entry

ChemComp-SIN:
SUCCINIC ACID / Succinic acid

ChemComp-HOH:
WATER / Water

Source
  • mus musculus (house mouse)
  • xenopus laevis (African clawed frog)
  • homo sapiens (human)
KeywordsSIGNALING 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

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