Structure of the TBC1D7-TSC1 complex reveals that TBC1D7 stabilizes dimerization of the TSC1 C-terminal coiled coil region

TSC1 and TSC2 mutations account for the majority of tuberous sclerosis complex cases. The TSC1 and TSC2 proteins assemble into a complex that is stabilized by TBC1D7 through its direct interaction with the TSC1 coiled coil (CC) region. Loss of TBC1D7 is associated with intellectual disability and megalencephaly. Here, we determine the crystal structure of the complex between TBC1D7 and the C-terminal part (residues 939-992) of TSC1-CC. The structure reveals that two TSC1-CCs form a parallel homodimer, which results in the formation of two symmetric surfaces for interaction with TBC1D7. TBC1D7 employs its α4 and α5 helices to interact with the α1 helix of one TSC1 (939-992) molecule mainly through hydrophobic interactions, and simultaneously associates with the other TSC1 (939-992) molecule using the C-terminal tip of its α4 helix. Biochemical and cell biological data demonstrate that TBC1D7 indeed substantially stabilizes the homodimerization of TSC1-CC, and mutations to the critical interface residues greatly compromise this effect. Together, our data reveal the molecular mechanism underlying TBC1D7-mediated stabilization of TSC1 dimerization, and its contribution to the structural integrity of the holo-TSC complex.