A dual binding mode for RhoGTPases in plexin signalling.

Abstract

Author SummaryAxon guidance is fundamental to the development of the central nervous system. The growing axon is guided to its correct location by a plethora of extracellular signals. One of the most important extracellular signals is semaphorin, which binds to plexin receptors on the axon. Usually, this kind of extracellular ligand binding is sufficient to transmit the extracellular signal to the intracellular space to trigger changes in the cell, like axon growth. However, activation of plexin receptors requires a “dual” ligand binding: semaphorin on the extracellular side, and a RhoGTPase on the intracellular side. Signal transduction can only occur if both ligands are present. How this intricate regulation mechanism is organized and how concomitant ligand binding can be integrated into a single signalling output within the cell has remained largely unclear. Here, we present crystal structures of one plexin receptor, Plexin-B1, in complex with an intracellular RhoGTPase ligand (Rac1) and show that binding of Rac1 brings together three Plexin-B1 molecules. In this trimeric arrangement each plexin molecule interacts with two Rac1 ligand molecules. This leads to a previously unidentified plexin-Rac1 ligand interface that is crucial for its function. Further biophysical and cellular analysis in combination with previous findings on the extracellular plexin-semaphorin complex allow us to propose a model for how ligand-induced clustering events on the extra- as well as intracellular side are combined to trigger signal transduction.