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

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 initiatio...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10089208/
https://www.ncbi.nlm.nih.gov/pubmed/36893265
http://dx.doi.org/10.1073/pnas.2218238120
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author 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
author_facet 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
author_sort Tsutsumi, Naotaka
collection PubMed
description 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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spelling pubmed-100892082023-04-12 Structure of the Wnt–Frizzled–LRP6 initiation complex reveals the basis for coreceptor discrimination 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 Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2023-03-09 2023-03-14 /pmc/articles/PMC10089208/ /pubmed/36893265 http://dx.doi.org/10.1073/pnas.2218238120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
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
Structure of the Wnt–Frizzled–LRP6 initiation complex reveals the basis for coreceptor discrimination
title Structure of the Wnt–Frizzled–LRP6 initiation complex reveals the basis for coreceptor discrimination
title_full Structure of the Wnt–Frizzled–LRP6 initiation complex reveals the basis for coreceptor discrimination
title_fullStr Structure of the Wnt–Frizzled–LRP6 initiation complex reveals the basis for coreceptor discrimination
title_full_unstemmed Structure of the Wnt–Frizzled–LRP6 initiation complex reveals the basis for coreceptor discrimination
title_short Structure of the Wnt–Frizzled–LRP6 initiation complex reveals the basis for coreceptor discrimination
title_sort structure of the wnt–frizzled–lrp6 initiation complex reveals the basis for coreceptor discrimination
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10089208/
https://www.ncbi.nlm.nih.gov/pubmed/36893265
http://dx.doi.org/10.1073/pnas.2218238120
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