The Structure of GATOR1–Rag GTPases Reveal Modes of Regulation

The mTORC1 pathway regulates cell growth and is frequently dysregulated in cancer. Nutrients signal though the heterodimeric Rag GTPases (RAGA or RAGB binds to RAGC or RAGD) to activate mTORC1. The GATOR1 protein complex, which is comprised of DEPDC5, NPRL2, and NPRL3, is a GTPase-activating protein (GAP) that acts on RAGA and RAGB. Loss of GATOR1 desensitizes mTORC1 to nutrient starvation, but its molecular structure and function remain unknown. Shen, Huang, and colleagues used cryo-electron microscopy to determine the structure of GATOR1 and GATOR1–RAG GTPases complexes to 4.4 Å and 4 Å, respectively. Purified GATOR1 promoted GTP hydrolysis by RAGA, and an intact GATOR1 was required for its GAP function and suppression of mTORC1 activity in response to nutrient deficiency. GATOR1 adopted an extended architecture with a central cavity; NPRL2 linked DEPDC5 to NPRL3. DEPDC5 interacted with the Rag GTPase heterodimer via three hydrogen bonds, and this interaction inhibited GATOR1-mediated stimulation of GTP hydrolysis by RAGA, suggesting the presence of an alternative interaction that promotes GAP activity. Indeed, a weaker interaction was identified between the NPRL2–NPRL3 heterodimer and RAGA that promoted GAP activity. These findings suggest two interaction modes: a Rag GTPases–DEPDC5 strong affinity inhibitory interaction with low GAP activity, and a Rag GTPases–NPRL2–NPRL3 weaker affinity interaction with higher GAP activity. Consistent with this model, disrupting the GAP inhibitory Rag GTPases–DEPDC5 interaction suppressed mTORC1 signaling in an NPRL2–NPRL3-dependent manner. Collectively, these findings elucidate the structural mechanism by which GATOR1 is regulated and reveal an inhibitory mode that may prevent GATOR1 hyperactivation.

Shen K, Huang RK, Brignole EJ, Condon KJ, Valenstein ML, Chantranupong L, et al. Architecture of the human GATOR1 and GATOR1-Rag GTPases complexes. Nature 2018;556:64–9.

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