Autoregulation of Sec7 Arf-GEF activity and localization by positive feedback

Members of the highly conserved Arf family of small GTPases serve as master regulators of vesicular transport. In yeast, Arf1 acts at the Golgi and trans-Golgi network (TGN) to recruit vesicular coat proteins and other effectors for both anterograde and retrograde transport. Arf1 is activated at the TGN by Sec7, the founding member of the Sec7 family of guanine nucleotide exchange factors (GEFs) and a close homolog of the human ARFGEF2 implicated in congenital defects in cerebral cortex development. Through the use of purified Sec7 in biochemical assays, we recently discovered that autoinhibition of Sec7 is relieved by stable recruitment to lipid membranes by activated Arf1. This interaction is mediated by a conserved domain proximal to, but not including, the GEF domain, creating a positive feedback loop in the activation of Arf1 at the TGN. We further demonstrated that this stable interaction with Arf1 plays a role in localizing Sec7 to the TGN. We elaborate here on the implications of these results to small GTPase-mediated cellular processes and coincidence detection models of GEF localization.