Shi, F., Mendrola, J.M., Sheetz, J.B., Wu, N., Sommer, A., Speer, K.F., Noordermeer, J.N., Kan, Z.Y., Perry, K., Englander, S.W., Stayrook, S.E., Fradkin, L.G., Lemmon, M.A. (2021). ROR and RYK extracellular region structures suggest that receptor tyrosine kinases have distinct WNT-recognition modes.  Cell Rep. 37(3): 109834.

FBrf0251592

Research paper

WNTs play key roles in development and disease, signaling through Frizzled (FZD) seven-pass transmembrane receptors and numerous co-receptors including ROR and RYK family receptor tyrosine kinases (RTKs). We describe crystal structures and WNT-binding characteristics of extracellular regions from the Drosophila ROR and RYK orthologs Nrk (neurospecific receptor tyrosine kinase) and Derailed-2 (Drl-2), which bind WNTs though a FZD-related cysteine-rich domain (CRD) and WNT-inhibitory factor (WIF) domain respectively. Our crystal structures suggest that neither Nrk nor Drl-2 can accommodate the acyl chain typically attached to WNTs. The Nrk CRD contains a deeply buried bound fatty acid, unlikely to be exchangeable. The Drl-2 WIF domain lacks the lipid-binding site seen in WIF-1. We also find that recombinant DWnt-5 can bind Drosophila ROR and RYK orthologs despite lacking an acyl chain. Alongside analyses of WNT/receptor interaction sites, our structures provide further insight into how WNTs may recruit RTK co-receptors into signaling complexes.

PMC8650758 (PMC) (EuropePMC)