Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace

mTORC1 is a kinase complex regulating cell growth, proliferation and survival. Because mis-regulation of DEPTOR, an endogenous mTORC1 inhibitor, is associated with some cancers, we reconstituted mTORC1 with DEPTOR to understand its function. We find that DEPTOR is a uniquepartialmTORC1 inhibitor that may have evolved to preserve feedback inhibition of PI3K. Counterintuitively, mTORC1 activated by RHEB or oncogenic mutation is much more potently inhibited by DEPTOR. Although DEPTOR partially inhibits mTORC1, mTORC1 prevents this inhibition by phosphorylating DEPTOR, a mutual antagonism that requires no exogenous factors. Structural analyses of the mTORC1/DEPTOR complex showed DEPTOR’s PDZ domain interacting with the mTOR FAT region, and the unstructured linker preceding the PDZ binding to the mTOR FRB domain. Here we show, in contrast to previous cellular studies, that both the PDZ and linker regions are essential for inhibition, and it is likely that interaction with the FRB is crucial to the unique partial inhibition.