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

Cell reports 2021 Oct 19

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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. Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Fumin Shi, Jeannine M Mendrola, Joshua B Sheetz, Neo Wu, Anselm Sommer, Kelsey F Speer, Jasprina N Noordermeer, Zhong-Yuan Kan, Kay Perry, S Walter Englander, Steven E Stayrook, Lee G Fradkin, Mark A Lemmon. ROR and RYK extracellular region structures suggest that receptor tyrosine kinases have distinct WNT-recognition modes. Cell reports. 2021 Oct 19;37(3):109834