Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling
- University of Oxford, United Kingdom
- University of California, Davis, United States
- Diamond Light Source, United Kingdom
- University of Waterloo, Canada
Abstract
The receptor tyrosine kinase ROR2 mediates noncanonical WNT5A signaling to orchestrate tissue morphogenetic processes, and dysfunction of the pathway causes Robinow syndrome, Brachydactyly B and metastatic diseases. The domain(s) and mechanisms required for ROR2 function, however, remain unclear. We solved the crystal structure of the extracellular cysteine-rich (CRD) and Kringle (Kr) domains of ROR2 and found that, unlike other CRDs, the ROR2 CRD lacks the signature hydrophobic pocket that binds lipids/lipid-modified proteins, such as WNTs, suggesting a novel mechanism of ligand reception. Functionally, we showed that the ROR2 CRD, but not other domains, is required and minimally sufficient to promote WNT5A signaling, and Robinow mutations in the CRD and the adjacent Kr impair ROR2 secretion and function. Moreover, using function-activating and -perturbing antibodies against the Frizzled (FZ) family of WNT receptors, we demonstrate the involvement of FZ in WNT5A-ROR signaling. Thus, ROR2 acts via its CRD to potentiate the function of a receptor super-complex that includes FZ to transduce WNT5A signals.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Funding
National Institutes of Health (1R35GM119574)
- Hsin-Yi Henry Ho
National Institutes of Health (1R35GM144341)
- Hsin-Yi Henry Ho
Cancer Research UK (C20724/A26752)
- Christian Siebold
Wellcome Trust (203141/Z/16/Z)
- Christian Siebold
Wellcome Trust (099675/Z/12/Z)
- Samuel C Griffiths
National Institutes of Health (2P30CA093373-19)
- Hsin-Yi Henry Ho
Cancer Research UK (DRCRPG-May23/100002)
- Christian Siebold
National Institutes of Health (S10 OD018223)
- Hsin-Yi Henry Ho
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#21394) of the University of California, Davis. The protocol was approved by the IACUC of the University of California, Davis.
Copyright
© 2024, Griffiths et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling
eLife 13:e71980.
https://doi.org/10.7554/eLife.71980
