Structural insights into TSC complex assembly and GAP activity on Rheb

Abstract Tuberous sclerosis complex (TSC) integrates upstream stimuli and regulates cell growth by controlling the activity of mTORC1. TSC functions as a GTPase-activating protein (GAP) towards small GTPase Rheb inhibits Rheb-mediated activation Mutations in genes cause tuberous sclerosis. In this study, near-atomic resolution structure human reveals an arch-shaped architecture, with 2:2:1 stoichiometry TSC1, TSC2, TBC1D7. This asymmetric consists two interweaved TSC1 coiled-coil one TBC1D7 that spans over tail-to-tail TSC2 dimer. The GAP domains are symmetrically cradled within core module formed dimerization domain central TSC1. Structural biochemical analyses reveal GAP-Rheb complimentary interactions suggest catalytic mechanism, which asparagine thumb (N1643) stabilizes γ-phosphate GTP accelerate hydrolysis Rheb. Our study mechanisms assembly activity.