ROR and RYK extracellular region structures suggest that receptor tyrosine kinases have distinct WNT-recognition modes

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.

doi:10.1101/2021.04.29.442059

bioRxiv · 10.1101/2021.04.29.442059

ROR and RYK extracellular region structures suggest that receptor tyrosine kinases have distinct WNT-recognition modes

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.

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Abstract

SUMMARYWNTs play key roles in development and disease, by binding both Frizzled (FZD) seven-pass transmembrane receptors and numerous co-receptors that include the ROR and RYK 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). RORs bind WNTs though a FZD-related cysteine-rich domain (CRD), and RYKs through a WNT-inhibitory factor (WIF) domain. Our structures suggest that neither the Nrk CRD nor the Drl-2 WIF domain can accommodate the acyl chain typically attached to WNTs. The Nrk CRD contains a deeply buried bound fatty acid, unlikely to be exchangeable with a WNT acyl chain. The Drl-2 WIF domain lacks the lipid-binding site seen in WIF-1. We also show that DWnt-5, which regulates Drosophila ROR and RYK orthologs, lacks an acyl chain. Together with analysis of WNT/receptor interaction sites, these structures provide new insight into how WNTs recruit their RTK co-receptors into signaling complexes.

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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.. 2021-04-30. ROR and RYK extracellular region structures suggest that receptor tyrosine kinases have distinct WNT-recognition modes. https://doi.org/10.1101/2021.04.29.442059

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