Leucine-sensing mechanism of leucyl-tRNA synthetase 1 for mTORC1 activation

Sulhee Kim, Ina Yoon, Jonghyeon Son, Junga Park, Kibum Kim, Ji Ho Lee, Sam Yong Park, Beom Sik Kang, Jung Min Han, Kwang Yeon Hwang, Sunghoon Kim

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


Leucyl-tRNA synthetase 1 (LARS1) mediates activation of leucine-dependent mechanistic target of rapamycin complex 1 (mTORC1) as well as ligation of leucine to its cognate tRNAs, yet its mechanism of leucine sensing is poorly understood. Here we describe leucine binding-induced conformational changes of LARS1. We determine different crystal structures of LARS1 complexed with leucine, ATP, and a reaction intermediate analog, leucyl-sulfamoyl-adenylate (Leu-AMS), and find two distinct functional states of LARS1 for mTORC1 activation. Upon leucine binding to the synthetic site, H251 and R517 in the connective polypeptide and 50FPYPY54 in the catalytic domain change the hydrogen bond network, leading to conformational change in the C-terminal domain, correlating with RagD association. Leucine binding to LARS1 is increased in the presence of ATP, further augmenting leucine-dependent interaction of LARS1 and RagD. Thus, this work unveils the structural basis for leucine-dependent long-range communication between the catalytic and RagD-binding domains of LARS1 for mTORC1 activation.

Original languageEnglish
Article number109031
JournalCell Reports
Issue number4
Publication statusPublished - 2021 Apr 27


  • X-ray crystallography
  • conformational change
  • leucine sensing
  • leucyl-tRNA synthetase 1
  • mechanistic target of rapamycin complex 1

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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