Functional Modulation of a G Protein-Coupled Receptor Conformational Landscape in a Lipid Bilayer

Coordination between membrane trafficking and actin polymerization is fundamental in cell migration, but a dynamic view of the underlying molecular mechanisms is still missing. The Rac1 GTPase controls actin polymerization at protrusions by interacting with its effector, the Wave Regulatory Complex (WRC). The Exocyst complex, which functions in polarized exocytosis, has been involved in regulation of cell motility. Here we show a physical and functional connection between Exocyst and WRC. Purified components of Exocyst and WRC complexes directly associate in vitro and interactions interfaces are identified. The Exocyst/WRC interaction is confirmed in cells by co-immunoprecipitation and is shown to occur independently of the Arp2/3 complex. Disruption of the Exocyst/WRC interaction leads to impaired migration. By time-lapse microscopy coupled to image correlation analysis, we visualize the traffic of WRC toward the front in nascent protrusions. Exocyst is necessary for WRC recruitment at the leading edge and for resulting cell edge movements. This direct link between Exocyst and WRC complexes provides a novel mechanistic insight into the spatiotemporal regulation of cell migration.