Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability.
Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability.
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DOI：
10.1016/j.molcel.2017.09.026
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发表时间：
2017-11-02
期刊：
影响因子：
16
通讯作者：
Sabatini DM
中科院分区：
文献类型：
--
作者：
Shen K;Choe A;Sabatini DM
mTORC1 是一种中央生长调节剂，通过汇聚到 Rag GTPases（两种相关 GTPase 的专性异二聚体）的途径来感知氨基酸。尽管 Rag GTP 酶在氨基酸传感中发挥核心作用，但仍不清楚为什么 Rag GTP 酶是异二聚体以及它们的亚基是否相互通信。在这里，我们发现 GTP 与一个亚基的结合会抑制该结合并诱导另一个亚基对 GTP 的水解。这种子单元间通信将 Rag GTPases 推入两种稳定配置中的任一种，这两种稳定配置代表通过瞬态中间体相互转换的活跃“开”或“关”状态。亚基偶联赋予 mTORC1 通路快速响应氨基酸水平的能力。因此，mTORC1 的动态响应需要 Rag GTPases 进行亚基间通讯，这为它们以二聚体形式存在提供了基本原理，并揭示了 GTP 结合蛋白的独特控制模式。 Rag GTPase 异二聚体将氨基酸信号传递至 mTORC1。由于其专性异二聚体性质，它与典型的小信号 GTP 酶不同。沉等人。利用动力学方法分析了 Rag GTPase 亚基之间的通讯，揭示了控制其核苷酸状态的独特亚基间锁定机制。
mTORC1 is a central growth regulator that senses amino acids through a pathway that converges on the Rag GTPases, an obligate heterodimer of two related GTPases. Despite their central role in amino acid sensing, it is unknown why the Rag GTPases are heterodimeric and if their subunits communicate with each other. Here, we find that the binding of GTP to one subunit inhibits the binding and induces the hydrolysis of GTP by the other. This intersubunit communication pushes the Rag GTPases into either of two stable configurations, which represent active “on” or “off” states that interconvert via transient intermediates. Subunit coupling confers on the mTORC1 pathway its capacity to respond rapidly to the amino acid level. Thus, the dynamic response of mTORC1 requires intersubunit communication by the Rag GTPases, providing a rationale for why they exist as a dimer and revealing a distinct mode of control for a GTP-binding protein. The Rag GTPase heterodimer transmits amino acid signals to mTORC1. It is distinct from canonical small signaling GTPases because of its obligate heterodimeric nature. Shen et al. used the kinetic method to analyze communication between Rag GTPase subunits, revealing a unique intersubunit locking mechanism that controls its nucleotide state.
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