PT  - JOURNAL ARTICLE
AU  - Samuel C. Griffiths
AU  - Jia Tan
AU  - Armin Wagner
AU  - Levi Blazer
AU  - Jarret J. Adams
AU  - Sachdev S. Sidhu
AU  - Christian Siebold
AU  - Hsin-Yi Henry Ho
TI  - Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling
AID  - 10.1101/2021.07.26.453829
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.07.26.453829
4099  - http://biorxiv.org/content/early/2021/07/26/2021.07.26.453829.short
4100  - http://biorxiv.org/content/early/2021/07/26/2021.07.26.453829.full
AB  - 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 receptor action. 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 alter ROR2 function. Moreover, we demonstrated that the activity of the ROR2 CRD requires Frizzled receptors. Thus, ROR2 acts via its CRD to potentiate the function of a receptor supercomplex that includes Frizzleds to transduce WNT5A signals.Competing Interest StatementThe authors have declared no competing interest.