Structures and pH-dependent dimerization of the sevenless receptor tyrosine kinase

Gabriele Cerutti; Ronald Arias; Fabiana Bahna; Seetha Mannepalli; Phinikoula S Katsamba; Goran Ahlsen; Brian Kloss; Renato Bruni; Andrew Tomlinson; Lawrence Shapiro

doi:10.1016/j.molcel.2024.10.017

Structures and pH-dependent dimerization of the sevenless receptor tyrosine kinase

Mol Cell. 2024 Nov 6:S1097-2765(24)00857-8. doi: 10.1016/j.molcel.2024.10.017. Online ahead of print.

Authors

Affiliations

¹ Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA.
² Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Department of Genetics and Development, Columbia University, New York, NY 10027, USA.
³ Department of Physiology and Cellular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
⁴ New York Structural Biology Center, New York, NY 10027, USA.
⁵ Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Department of Genetics and Development, Columbia University, New York, NY 10027, USA. Electronic address: at41@columbia.edu.
⁶ Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Department of Biochemistry and Molecular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address: lss8@columbia.edu.

PMID: 39510067
DOI: 10.1016/j.molcel.2024.10.017

Abstract

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.

Keywords: ROS1; bride of sevenless; cell signaling; cryo-electron microscopy; developmental biology; eye development; protein-protein interaction; receptor tyrosine kinase; sevenless; structural biology.