Glu592 of the axon guidance receptor ROBO3 mediates a pH-dependent interaction with NELL2 ligand.

There are only a few studies on the function of neuronal axon guidance molecules during low brain pH conditions. We previously reported that roundabout (ROBO) 2, a receptor for the axon guidance molecule SLIT, can bind to the neural epidermal growth factor-like-like (NELL) ligands in acidic conditions by conformational change of its ectodomain. Here, we show that the ROBO3 receptor also exhibits a pH-dependent increase in binding to the NELL2 ligand. We found that the Glu592 residue of ROBO3 at the binding interface between NELL2 and ROBO3 is a pH sensor and that the formation of a new hydrogen bonding network, due to protonation of the Glu592, leads to increased binding in acidic conditions. These results suggest that NELL2-ROBO3 signaling could be regulated by extracellular pH.© 2024 The Author(s). FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Citation

Kimihiko Mizutani, Mayuko Toyoda, Teruyo Ojima-Kato, Andrés D Maturana, Tomoaki Niimi. Glu592 of the axon guidance receptor ROBO3 mediates a pH-dependent interaction with NELL2 ligand. FEBS letters. 2024 Nov 12

PMID: 39531524

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