Cryo-EM 结构的人类 GATOR1-Rag-Ragulator 复合物揭示了一种空间约束调控的 GAP 机制。
Cryo-EM structures of the human GATOR1-Rag-Ragulator complex reveal a spatial-constraint regulated GAP mechanism.
机构信息
Program in Molecular Medicine, University of Massachusetts Chan Medical School, 373 Plantation St, Worcester, MA 01605, USA.
Department of Biochemistry & Molecular Pharmacology, University of Massachusetts Chan Medical School, 364 Plantation St, Worcester, MA 01605, USA.
出版信息
Mol Cell. 2022 May 19;82(10):1836-1849.e5. doi: 10.1016/j.molcel.2022.03.002. Epub 2022 Mar 25.
mTORC1 controls cellular metabolic 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 the Ragulator complex. The Rag GTPases receive amino acid signals from multiple upstream regulators. One negative regulator, GATOR1, is a GTPase activating protein (GAP) for RagA. GATOR1 binds to the Rag GTPases via two modes: an inhibitory mode and a GAP mode. 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 binding sites simultaneously. When the Rag GTPases bind to GATOR1 at the GAP site, both Rag subunits contact GATOR1 to coordinate their nucleotide loading states. These results reveal a potential GAP mechanism of GATOR1 during the mTORC1 inactivation process.
mTORC1 可响应营养物质可用性来控制细胞代谢过程。氨基酸信号通过 Rag GTPases 传递到 mTORC1，而 Rag GTPases 则通过 Ragulator 复合物定位于溶酶体表面。Rag GTPases 从多个上游调节剂接收氨基酸信号。一种负调节剂 GATOR1 是 RagA 的 GTPase 激活蛋白 (GAP)。GATOR1 通过两种模式与 Rag GTPases 结合：抑制模式和 GAP 模式。这两种结合相互作用如何协调氨基酸信号的处理尚不清楚。在这里，我们解析了 GATOR1-Rag-Ragulator 复合物的三个冷冻电镜结构模型，其中 Rag-Ragulator 亚复合物占据抑制位点、GAP 位点和两个结合位点。当 Rag GTPases 在 GAP 位点与 GATOR1 结合时，两个 Rag 亚基都与 GATOR1 接触，以协调它们的核苷酸加载状态。这些结果揭示了 GATOR1 在 mTORC1 失活过程中的潜在 GAP 机制。
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