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

doi:10.1073/pnas.2218238120

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

Journal Article · Thu Mar 09 00:00:00 EST 2023 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.2218238120· OSTI ID:2003210

^[1]; Hwang, Sunhee ^[2]; Waghray, Deepa ^[3]; Hansen, Simon ^[2]; ^[3]; ^[3]; Miao, Yi ^[3]; Glassman, Caleb R. ^[3]; ^[3]; Janda, Claudia Y. ^[4]; ^[2]; ^[3]

Stanford Univ., CA (United States). School of Medicine; Okayama Univ. (Japan); SLAC
Genentech, San Francisco, CA (United States)
Stanford Univ., CA (United States). School of Medicine
Stanford Univ., CA (United States). School of Medicine; Princess Maxima Center for Pediatric Oncology, Utrecht (Netherlands)

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.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS); SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Sponsoring Organization:: National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-05CH11231; AC02-76SF00515

OSTI ID:: 2003210

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 11 Vol. 120; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

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