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Cited by 52Wnt/β-catenin signaling in development and cancerReceptor Mechanisms and SignalingDevelopmental Biology and Gene Regulation

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Structure of the Wnt–Frizzled–LRP6 initiation complex reveals the basis for coreceptor discrimination

Open access
Tsutsumi, Naotaka, Hwang, Sunhee, Waghray, Deepa, Hansen, Simon, Jude, Kevin M., Wang, Nan, Miao, Yi, Glassman, Caleb R., Caveney, Nathanael A., Janda, Claudia Y., Hannoush, Rami N., Garcia, K. Christopher·2023·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2218238120PMC PMC10089208

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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 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.

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Metadata

Authors
Tsutsumi, N., Hwang, S., Waghray, D., Hansen, S., Jude, K. M., Wang, N., Miao, Y., Glassman, C. R., Caveney, N. A., Janda, C. Y., Hannoush, R. N., & Garcia, K. C.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Genentech (US)
  • Stanford Medicine (US)
  • Princess Máxima Center (NL)
  • HHMI, Stanford University School of Medicine, Stanford, CA 94305
Corresponding author
Hannoush, Rami N.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2023-03-09
Volume
120
Issue
11
Pages
e2218238120-e2218238120
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2218238120
PMC
PMC10089208
OpenAlex
W4323656687
Cited by
52
References
1
Citations by year
2026: 15 · 2025: 16 · 2024: 16 · 2023: 5
FWCI
4.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
  • HHS | National Institutes of Health (R01DK115728)
  • Howard Hughes Medical Institute (none)
  • Ludwig Institute for Cancer Research (none)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
Wnt signaling, Frizzled receptors, LRP6, ternary receptor complex, Wnt8, Wnt5a, non-canonical Wnt signaling, Wnt antagonists, β-catenin signaling, signalosome
MeSH terms
Cell Membrane, Signal Transduction, Wnt Proteins, Frizzled Receptors, beta Catenin, Wnt Signaling Pathway, Low Density Lipoprotein Receptor-Related Protein-6

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