Loop modelling provides insights into regulation of mTORC1 activity via DEPTOR dimerisation

Abstract

mTOR regulates cell growth by forming the mTORC1 and mTORC2 complexes. DEPTOR partially inhibits mTORC1, which in turn phosphorylates and inactivates it. Despite the mTORC1–DEPTOR structures, the exact mechanism remains unclear largely because functionally flexible key elements, DEPTOR’s linker in particular, are unresolved. By taking DEPTOR’s dimerisation into consideration, our modelling of these missing loops suggests that monomeric DEPTOR bound to mTORC1 in a non-inhibitory mode, while the domain-swapped dimeric DEPTOR could interact with mTORC1’s FRB domain and block the kinase’s catalytic site with its linker. These two states indicate that linker phosphorylation inactivates DEPTOR possibly by disrupting its dimerisation, which could tether the linker to the kinase domain to enhance mTORC1 inhibition. In addition to DEPTOR, mTOR’s kα9b–kα10 loop, which harbours the S2481 autophosphorylation site, and mSIN1’s flexible domains in mTORC2 might act as inhibitory elements too.