Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway.
Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway.
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DOI：
10.1126/science.aad2087
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发表时间：
2016-01-01
期刊：
影响因子：
--
通讯作者：
Sabatini DM
中科院分区：
文献类型：
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作者：
Saxton RA;Knockenhauer KE;Wolfson RL;Chantranupong L;Pacold ME;Wang T;Schwartz TU;Sabatini DM
真核细胞通过mTOR复合物1（mTORC 1）（一种主要生长调节剂）协调生长与营养物质的可用性。亮氨酸特别重要，并通过Rag GTP酶及其调节剂GATOR 1和GATOR 2激活mTORC 1。Sestrin 2与GATOR 2相互作用，是亮氨酸传感器。我们提出了与亮氨酸复合的Sestrin 2的2.7-ε晶体结构。亮氨酸通过单个口袋结合，该口袋协调其带电官能团并赋予疏水侧链特异性。环包围亮氨酸并形成结合所需的盖闩锁机制。Sestrin 2中的结构引导突变降低了其对亮氨酸的亲和力，导致细胞中mTORC 1活化所需的亮氨酸浓度随之增加。这些结果提供了mTORC 1途径的氨基酸传感的结构机制。
Eukaryotic cells coordinate growth with the availability of nutrients through mTOR complex 1 (mTORC1), a master growth regulator. Leucine is of particular importance and activates mTORC1 via the Rag GTPases and their regulators GATOR1 and GATOR2. Sestrin2 interacts with GATOR2 and is a leucine sensor. We present the 2.7-Å crystal structure of Sestrin2 in complex with leucine. Leucine binds through a single pocket that coordinates its charged functional groups and confers specificity for the hydrophobic side chain. A loop encloses leucine and forms a lid-latch mechanism required for binding. A structure-guided mutation in Sestrin2 that decreases its affinity for leucine leads to a concomitant increase in the leucine concentration required for mTORC1 activation in cells. These results provide a structural mechanism of amino acid sensing by the mTORC1 pathway.