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塞斯特林2是mTORC1通路的白蛋白传感器

Rachel L Wolfson¹, Lynne Chantranupong¹, Robert A Saxton¹

¹Whitehead 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.

Science (New York, N.Y.)

|October 10, 2015

概括

氨酸通过与Sestrin2结合激活mTORC1通路,从而破坏其与GATOR2的相互作用. 这种结合对白来说是必不可少的,它标识了Sestrin2作为一个关键的白传感器.

科学领域:

细胞生物学
分子信号
哺乳动物生理学

背景情况:

氨酸是一种关键的氨基酸,通过激活mTOR复合体1 (mTORC1) 途径来调节哺乳动物生理.
对mTORC1的氨基酸信号涉及Rag GTPases,由包括GATOR1,GATOR2和Sestrin2在内的因素调节.
已知Sestrin2通过与GATOR2相互作用来抑制mTORC1的信号传递.

研究的目的:

阐明白激活mTORC1通路的精确机制.
调查Sestrin2在调解白氨酸对mTORC1信号的作用.
为了确定Sestrin2是否可以作为leucine的直接传感器.

主要方法:

生物化学测试以测量蛋白质相互作用和结合亲和力.
细胞实验以评估mTORC1通路的激活反应.
突变分析以评估氨酸与Sestrin的结合的重要性2.

主要成果:

氨酸直接与Sestrin2结合,解离常数 (Kd) 为20微米.
这种素结合会破坏Sestrin2和GATOR2之间的相互作用.
塞斯特林2的素结合能力对于细胞中素诱导的mTORC1激活至关重要.

结论:

塞斯特林2作为mTORC1通路的直接白蛋白传感器.
素与Sestrin2的结合是mTORC1激活的启动事件.
这一发现揭示了营养感应和生长控制的新机制.

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