Rag GTP酶异二聚体中的亚基间串扰使mTORC1能够快速响应氨基酸可用性。
Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability.
作者信息
Shen Kuang, Choe Abigail, Sabatini David M
机构信息
Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA.
Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA.
出版信息
Mol Cell. 2017 Nov 2;68(3):552-565.e8. doi: 10.1016/j.molcel.2017.09.026. Epub 2017 Oct 19.
mTOR complex I (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 whether their subunits communicate with each other. Here, we find that the binding of guanosine triphosphate (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.
mTOR 复合体 I（mTORC1）是一种核心生长调节因子，它通过一条汇聚于 Rag GTP 酶的途径感知氨基酸，Rag GTP 酶是由两个相关 GTP 酶组成的 obligate 异二聚体。尽管它们在氨基酸感知中起核心作用，但 Rag GTP 酶为何是异二聚体以及它们的亚基之间是否相互通讯仍不清楚。在这里，我们发现三磷酸鸟苷（GTP）与一个亚基的结合会抑制另一个亚基的结合并诱导其 GTP 水解。这种亚基间通讯将 Rag GTP 酶推向两种稳定构象中的一种，这两种构象分别代表通过瞬时中间体相互转化的活性“开”或“关”状态。亚基偶联赋予 mTORC1 途径对氨基酸水平快速响应的能力。因此，mTORC1 的动态响应需要 Rag GTP 酶进行亚基间通讯，这为它们为何以二聚体形式存在提供了理论依据，并揭示了一种 GTP 结合蛋白独特的控制模式。
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