Cerutti, G., Arias, R., Bahna, F., Mannepalli, S., Katsamba, P.S., Ahlsen, G., Kloss, B., Bruni, R., Tomlinson, A., Shapiro, L. (2024). Structures and pH-dependent dimerization of the sevenless receptor tyrosine kinase.  Mol. Cell 84(23): 4677--4690.e6.

FBrf0261119

Research paper

Sevenless (Sev) is a Drosophila receptor tyrosine kinase (RTK) required for the specification of the R7 photoreceptor. It is cleaved into α and β subunits and binds the ectodomain of the G-protein-coupled receptor bride of sevenless (Boss). Previous work showed that the Boss ectodomain could bind but not activate Sev; rather, the whole seven-pass transmembrane Boss was required. Here, we show that Sev does not need to be cleaved to function and that a single-pass transmembrane form of Boss activates Sev. We use cryo-electron microscopy and biophysical methods to determine the structural basis of ligand binding and pH-dependent dimerization of Sev, and we discuss the implications in the process of Sev activation. The Sev human homolog, receptor oncogene from sarcoma 1 (ROS1), is associated with oncogenic transformations, and we discuss their structural similarities.

PMC11625006 (PMC) (EuropePMC)