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- W3091967646 abstract "Abstract mTORC1 is a major regulator for cell growth and proliferation that coordinates nutrient inputs, such as amino acids, glucose, and growth factor, with anabolic and catabolic processes in cells. Amino acid signals are transmitted towards mTORC1 through the Rag GTPases, which directly recruit mTORC1 onto the lysosomal membrane. The Rag GTPase heterodimer has a unique architecture that consists of two GTPase subunits, RagA or RagB bound to RagC or RagD. Their nucleotide loading states are strictly controlled by several lysosomal or cytosolic protein complexes that directly process the amino acid signal. One such complex is GATOR1, a negative regulator on the cytosolic branch of the amino acid sensing pathway. GATOR1 comprises three subunits, Depdc5, Nprl2, and Nprl3, and is a GTPase Activating Protein (GAP) for RagA. It functions through a noncanonical GAP mechanism in which GATOR1 binds the Rag GTPases with two modes, an inhibitory mode that holds the Rag GTPase heterodimer and has been captured by structural determination, and a GAP mode that actually stimulates GTP hydrolysis by RagA but remains elusive. Here, we used biochemical approaches to probe the GAP mode of GATOR1 and found that a critical arginine finger on Nprl2, Arg78, is the catalytic residue, while a loop localized close to it provides the binding site for the Rag GTPases. Furthermore, we used cryo-EM to resolve the structure of the GATOR1-Rag-Ragulator complex at 4.1A resolution, which represents the architecture of the mTORC1-inhibiting complex on the lysosomal surface. Our results revealed the molecular bases for mTORC1 inactivation in human cells. This abstract is also being presented as Poster B10. Citation Format: Kuang Shen, Rick Huang, Zhiheng Yu, David M. Sabatini. Structural and functional analyses of GATOR1, a negative regulator of the mTORC1 pathway [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr PR02." @default.
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- W3091967646 date "2020-10-01" @default.
- W3091967646 modified "2023-10-05" @default.
- W3091967646 title "Abstract PR02: Structural and functional analyses of GATOR1, a negative regulator of the mTORC1 pathway" @default.
- W3091967646 doi "https://doi.org/10.1158/1557-3125.pi3k-mtor18-pr02" @default.
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