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bioRxiv · 10.1101/2022.10.21.513178

Structure of the Wnt-Frizzled-LRP6 initiation complex reveals the basis for co-receptor discrimination

Tsutsumi, N.·Hwang, S.·Hansen, S.·Waghray, D.·Wang, N.·Miao, Y.·Glassman, C. R.·Caveney, N. A.·Jude, K. M.·Janda, C. Y.·Hannoush, R.·Garcia, K. C.
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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 receptors together with the shared LRP5/6 co-receptors to initiate {beta}-catenin signaling. The structure of a ternary complex of an affinity-matured XWnt8-Frizzled8-LRP6 complex elucidates the basis of co-receptor 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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Tsutsumi, N., Hwang, S., Hansen, S., Waghray, D., Wang, N., Miao, Y., Glassman, C. R., Caveney, N. A., Jude, K. M., Janda, C. Y., Hannoush, R., Garcia, K. C.. 2022-10-22. Structure of the Wnt-Frizzled-LRP6 initiation complex reveals the basis for co-receptor discrimination. https://doi.org/10.1101/2022.10.21.513178

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