Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling

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 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.

Long-term single molecule localization microscopy uncovers dynamic co-assembly of Lrp6 and Ror2 into Wnt-signalosomes

“…While originally known as 'orphan' receptor, Wnt5a was identified to be the ligand of Ror2 [20], and Ror1/2 have a Fzd-related CRD. However, structures of Ror2-CRD show it is either pre-occupied by a fatty acid [21] or lack the hydrophobic binding pocket [22]. This indicates Wnt5a needs to engage Fzds (e.g.…”