Cryo-EM structures of the human GATOR1-Rag-Ragulator complex reveal a spatial-constraint regulated GAP mechanism.
Cryo-EM structures of the human GATOR1-Rag-Ragulator complex reveal a spatial-constraint regulated GAP mechanism.
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DOI：
10.1016/j.molcel.2022.03.002
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发表时间：
2022-05-19
期刊：
影响因子：
16
通讯作者：
Shen, Kuang
中科院分区：
文献类型：
--
作者：
Egri, Shawn B.;Ouch, Christna;Chou, Hui-Ting;Yu, Zhiheng;Song, Kangkang;Xu, Chen;Shen, Kuang
MTORC1控制细胞代谢过程以响应营养的可获得性。氨基酸信号通过RAG GTP酶传递到mTORC1，RAG GTP酶由Ragator复合体定位于溶酶体表面。Rag GTP酶从多个上游调节因子接收氨基酸信号。负调控因子GATOR1是RAGA的GTP酶激活蛋白(GAP)。GATOR1通过两种模式与Rag GTP酶结合：抑制模式和间隙模式。这两个结合作用是如何协调处理氨基酸信号的尚不清楚。在这里，我们解析了GATOR1-Rag-Ragator复合体的三种低温EM结构模型，其中Rag-Ragator亚复合体同时占据了抑制部位、间隙部位和两个结合部位。当RAG GTP酶在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负载状态。这些结果揭示了GATOR1在mTORC1失活过程中可能的GAP机制。GATOR1是mTORC1的负调控因子，它是如何在机制水平上抑制信号传递的，目前还知之甚少。在这里，Egri等人。描述GATOR1-RAG-Ragator复合体的三种结构模型。他们揭示，GATOR1调节两个RAG亚基的核苷酸状态，以调节mTORC1信号。
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. How GATOR1, a negative regulator of mTORC1, suppresses signaling on a mechanistic level has remained poorly understood. Here, Egri et al. describe three structural models of the GATOR1-Rag-Ragulator complex. They reveal that GATOR1 modulates the nucleotide status of both Rag subunits to regulate mTORC1 signaling.
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