| TBC1D7, a non-canonical member of the TBC/RabGAP protein family that lacks the typical catalytic arginine and glutamine fingers, serves as the third essential subunit of the TSC1-TSC2 complex, known as the TSC complex. By binding to the C-terminal coiled-coil domain of TSC1, TBC1D7 stabilizes the heterodimerization of TSC1 and TSC2 and enhances the Rheb-GAP activity required for effective mTORC1 suppression. TBC1D7 adopts a compact, globular fold composed of fifteen α-helices, with conserved residues on α4 and α5 mediating interaction with TSC1 through a 2:2 heterotetramer interface, where the C-terminal tip of α4 crosslinks adjacent TSC1 molecules, reinforcing the rigidity and stability of the complex. Phosphorylation of Ser124 by Akt enables recruitment of 14-3-3 proteins, further stabilizing TBC1D7. TBC1D7 is crucial for maintaining the integrity of the TSC complex, preventing TSC1 dissociation, and amplifying TSC2-mediated Rheb-GTP hydrolysis, thereby dampening mTORC1-driven anabolic pathways such as protein synthesis and cell growth and limiting lysosome-based mTORC1 activation during nutrient stress. TBC1D7 also fine-tunes autophagy, insulin and PI3K signaling responses, and systemic growth, with some functions occurring independently of the TSC complex. Loss of TBC1D7 destabilizes the TSC1-TSC2 complex, increases Rheb-GTP and mTORC1 activity, leads to cell enlargement, and delays autophagy, while mutations are linked to intellectual disability and abnormal brain growth due to mTORC1 hyperactivation. Disease associations include the augmentation of tuberous sclerosis complex and various neurodevelopmental disorders, with TBC1D7 deficiency mimicking the effects of TSC1 or TSC2 loss under nutrient-limiting conditions. |
