The mTORC1 kinase complex regulates 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 unique partial mTORC1 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. The linker and PDZ form the minimal inhibitory unit, but the N-terminal tandem DEP domains also significantly contribute to inhibition.

中文翻译：

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二分结合和部分抑制将 DEPTOR 和 mTOR 连接成相互对立的状态

mTORC1 激酶复合物调节细胞生长、增殖和存活。由于 DEPTOR（一种内源性 mTORC1 抑制剂）的错误调节与某些癌症相关，因此我们用 DEPTOR 重建了 mTORC1 以了解其功能。我们发现 DEPTOR 是一种独特的部分mTORC1 抑制剂，可能已经进化到保留 PI3K 的反馈抑制。与直觉相反，由 RHEB 或致癌突变激活的 mTORC1 被 DEPTOR 抑制得更有效。尽管 DEPTOR 部分抑制 mTORC1，但 mTORC1 通过磷酸化 DEPTOR 来阻止这种抑制，DEPTOR 是一种不需要外源因子的相互拮抗作用。mTORC1/DEPTOR 复合物的结构分析表明，DEPTOR 的 PDZ 结构域与 mTOR FAT 区域相互作用，并且 PDZ 之前的非结构化连接子与 mTOR FRB 结构域结合。连接子和 PDZ 形成最小抑制单元，但 N 端串联 DEP 结构域也对抑制有显着贡献。