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

Fumin Shi1, Jeannine M Mendrola2, Joshua B Sheetz3

  • 1Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.

Cell Reports
|October 23, 2021
PubMed

Insights

This study reveals that Drosophila ROR and RYK receptor tyrosine kinases (RTKs) can bind WNTs without their typical acyl chains. Structural analysis suggests these RTKs may not accommodate WNT lipid modifications, impacting signaling complex formation.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Structural Biology

Background:

  • WNT proteins are crucial signaling molecules in development and disease.
  • WNTs signal via Frizzled (FZD) receptors and co-receptors like ROR and RYK receptor tyrosine kinases (RTKs).

Purpose of the Study:

  • To determine the structural basis of WNT binding to Drosophila ROR (Nrk) and RYK (Drl-2) orthologs.
  • To investigate the role of WNT lipid modification in RTK co-receptor recruitment.

Main Methods:

  • X-ray crystallography was used to determine the structures of Nrk and Drl-2 extracellular regions.
  • WNT-binding assays were performed using recombinant proteins.

Main Results:

  • Crystal structures of Nrk and Drl-2 revealed they likely cannot accommodate the typical WNT acyl chain.
  • The Nrk cysteine-rich domain (CRD) has a buried fatty acid, and the Drl-2 WNT-inhibitory factor (WIF) domain lacks a lipid-binding site.
  • Recombinant DWnt-5 bound Nrk and Drl-2 even without an acyl chain.

Conclusions:

  • Drosophila ROR and RYK orthologs can bind WNTs lacking acyl chains, suggesting alternative binding mechanisms.
  • Structural insights into WNT/RTK interactions provide a basis for understanding WNT signaling complex assembly.
Keywords:
DrosophilaWNT signalingacylationcancerco-receptorgrowth factor signalingligandpseudokinasesreceptorreceptor tyrosine kinases

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