Exploring the Structure and Dynamics of All-Atom Models for the Plexin Transmembrane Receptor Bound to GTPases and to Lipid Bilayer

Abstract

Plexins are transmembrane receptors that receive guidance cues (such as binding of Semaphorin ligands) and are activated by them, functioning in cell migration processes in neuronal and cardiovascular development, but also in cancer metastasis. Plexins are unique, as they are the first example of a receptor that interacts directly with small GTPases, a family of proteins that are essential for cell motility and proliferation/survival. We previously determined the structure of the Rho GTPase binding domain (RBD) of several Plexins and also of the entire intracellular region of a Plexin-B1 [1]. Using all atom molecular dynamics we are characterizing how Rho and Ras GTPases influence the dynamics of the receptor [2]. Specifically, microsecond molecular dynamics simulations run on Anton, probe an allosteric network that changes upon plexin-B1 RBD dimerization and Rho GTPase binding. We also built models of the entire intracellular region, starting from several crystal structures linked to transmembrane helices [3], at different lipid membrane bilayers, with and without GTPases bound. The models and simulations reveal the origin of Ras and Rho specificity on plexin's function.