biostudies-literatureGriffiths SCCancer Research UKNCI NIH HHSNational Institutes of HealthWellcome TrustNIGMS NIH HHSNIH HHSe71980https://www.ebi.ac.uk/biostudies/studies/S-EPMC11219042biostudies-literatureUnknown13The 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 secreeLifeStructure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling.PMC1121904210.35802/09967526752DRCRPG-May23/100002C20724/A26752099675/Z/12/Z10.35802/2031411R35GM119574R35 GM144341203141/Z/16/ZS10 OD0182232031412P30CA093373-19P30 CA0933731R35GM144341R35 GM119574Ho HHBlazer LLTan JSidhu SSSrinivasan SGriffiths SCAdams JJWagner AMoghisaei SSiebold CfalseStructure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling.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 secre2024-01-01T00:00:00Z2024 May2026-06-01T21:27:09.942Z2025-04-04T12:22:04.471ZS-EPMC112190423878001110.7554/eLife.71980