Cryo‐EM structures of the Human GATOR1‐Rag‐Ragulator Complex Reveal a Spatial‐Constraint Regulated GAP Mechanism

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mTORC1 controls cellular processes in response to nutrient availability. Amino acid signals are transmitted to mTORC1 through the Rag GTPases, which are localized on the lysosomal surface by Ragulator. The Rag GTPases receive amino acid signals from upstream regulators. One negative regulator, GATOR1, is a GTPase activating protein (GAP) for RagA. GATOR1 binding to the Rag GTPases occurs via either of two modes: an inhibitory mode that has low enzymatic activity but high affinity, and a GAP mode that has high enzymatic activity but low affinity. How these two binding interactions coordinate to process amino acid signals is unknown. Here, we resolved three cryo‐EM structural models of the GATOR1‐Rag‐Ragulator complex, with the Rag‐Ragulator subcomplex occupying the inhibitory site, the GAP site, and both sites simultaneously. These structural models, together with the spatial constraints from the lysosomal membrane, reveal how GATOR1 coordinates the nucleotide loading states of both Rag subunits to transmit amino acid signals.