METABOLISM Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway

被引：350

作者：

Saxton, Robert A. ^{[1
,2
,3
,4
,5
]}

Knockenhauer, Kevin E. ^{[1
]}

Wolfson, Rachel L. ^{[1
,2
,3
,4
,5
]}

Chantranupong, Lynne ^{[1
,2
,3
,4
,5
]}

Pacold, Michael E. ^{[1
,2
,3
,4
,5
]}

Wang, Tim ^{[1
,2
,3
,4
,5
]}

Schwartz, Thomas U. ^{[1
]}

Sabatini, David M. ^{[1
,2
,3
,4
,5
]}

机构：

[1] MIT, Dept Biol, Cambridge, MA 02139 USA

[2] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[3] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02139 USA

[4] Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[5] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

来源：

SCIENCE | 2016年 / 351卷 / 6268期

基金：

美国国家卫生研究院;

关键词：

RAG GTPASES; SIGNAL INTEGRATION; AMINO-ACIDS; MTORC1; SESTRINS; ACTIVATION; PROTEIN; SUFFICIENCY; RAGULATOR; MECHANISM;

D O I：

10.1126/science.aad2087

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Eukaryotic cells coordinate growth with the availability of nutrients through the mechanistic target of rapamycin complex 1 (mTORC1), a master growth regulator. Leucine is of particular importance and activates mTORC1 via the Rag guanosine triphosphatases and their regulators GATOR1 and GATOR2. Sestrin2 interacts with GATOR2 and is a leucine sensor. Here we present the 2.7 angstrom 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.

引用

页码：53 / 58

页数：6

共 30 条

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