LAUSR

Brag2, which controls integrin endocytosis and cell adhesion and is impaired in cancer and developmental diseases. Brag2 activates Arf GTPases by stimulating the replacement of GDP by GTP, leading to the active, membraneattached form of Arf which recruits downstream effectors. We showed previously that, although Brag2 is highly active in solution, negatively charged membranes stimulate its efficiency by up to 3 orders of magnitude. We analyzed the determinants of this spectacular contribution of membranes by combining crystallography, coarse-grained molecular dynamics and reconstitution of Arf GTPases and Brag2 in artificial membranes. We found that the Arf/ Brag complex forms multiple interactions with charged lipids to organize a precise orientation of the complex with respect to the membrane that determines its activation kinetics. We discovered that this determinant can be harnessed by a new type of cell-active, allosteric inhibitors, that impair the orientation of the complex by binding at the GEF/lipid interface.