An interdomain hydrogen bond in the Rag GTPases maintains stable mTORC1 signaling in sensing amino acids.
An interdomain hydrogen bond in the Rag GTPases maintains stable mTORC1 signaling in sensing amino acids.
复制标题
DOI：
10.1016/j.jbc.2021.100861
复制
发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Shen K
中科院分区：
文献类型：
--
作者：
Egri SB;Shen K
细胞生长和增殖主要由雷帕霉素复合物1（mTORC 1）的机制靶点决定，该靶点平衡营养物质的可用性与细胞的合成代谢需求。mTORC 1活性的核心是RagA-RagC GTdR异二聚体，其在有利条件下将复合物募集到溶酶体表面以促进其活性。RagA-RagC异二聚体具有独特的结构，因为两个亚基都是活性GTP酶。为了促进mTORC 1活性，RagA亚基装载GTP，RagC亚基装载GDP，而相反的核苷酸装载构型抑制该信号传导途径。尽管其独特的分子结构，如何Rag GTd 3异源二聚体保持相反加载的核苷酸状态仍然难以捉摸。在这里，我们应用结构-功能分析方法的Rag GTPases异二聚体的晶体结构，并确定了一个关键的氢键，稳定的GDP负载状态的Rag GTPases。该氢键分别由RagA的核苷酸结合结构域中Asn 30的骨架羰基或RagC的Lys 84以及RagA的C-末端路障结构域中Thr 210的侧链上的羟基或RagC的Ser 266介导。消除这种结构域间氢键消除了Rag GT酶维持其功能状态的能力，导致对氨基酸信号的扭曲反应。我们的研究结果表明，这种长距离的结构域间相互作用的拉格GTdR的mTORC 1营养传感途径的维护和调节是必需的。
Cellular growth and proliferation are primarily dictated by the mechanistic target of rapamycin complex 1 (mTORC1), which balances nutrient availability against the cell’s anabolic needs. Central to the activity of mTORC1 is the RagA–RagC GTPase heterodimer, which under favorable conditions recruits the complex to the lysosomal surface to promote its activity. The RagA–RagC heterodimer has a unique architecture in that both subunits are active GTPases. To promote mTORC1 activity, the RagA subunit is loaded with GTP and the RagC subunit is loaded with GDP, while the opposite nucleotide-loading configuration inhibits this signaling pathway. Despite its unique molecular architecture, how the Rag GTPase heterodimer maintains the oppositely loaded nucleotide state remains elusive. Here, we applied structure–function analysis approach to the crystal structures of the Rag GTPase heterodimer and identified a key hydrogen bond that stabilizes the GDP-loaded state of the Rag GTPases. This hydrogen bond is mediated by the backbone carbonyl of Asn30 in the nucleotide-binding domain of RagA or Lys84 of RagC and the hydroxyl group on the side chain of Thr210 in the C-terminal roadblock domain of RagA or Ser266 of RagC, respectively. Eliminating this interdomain hydrogen bond abolishes the ability of the Rag GTPase to maintain its functional state, resulting in a distorted response to amino acid signals. Our results reveal that this long-distance interdomain interaction within the Rag GTPase is required for the maintenance and regulation of the mTORC1 nutrient-sensing pathway.
登录
查看更多内容
影响因子：
10.5
作者：
Inoki, K;Li, Y;Guan, KL
通讯作者：
Guan, KL
影响因子：
16
作者：
Shen K;Choe A;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
4.8
作者：
Jeong, Jae-Hee;Lee, Kwang-Hoon;Kim, Yeon-Gil
通讯作者：
Kim, Yeon-Gil
Gtr1p-Gtr2p 复合物的晶体结构揭示了氨基酸诱导的 TORC1 激活的新见解
影响因子：
10.5
作者：
Gong, Rui;Li, Li;Xu, Yanhui
通讯作者：
Xu, Yanhui
影响因子：
21.3
作者：
Kim, Eunjung;Goraksha-Hicks, Pankuri;Li, Li;Neufeld, Thomas P.;Guan, Kun-Liang
通讯作者：
Guan, Kun-Liang