Journal
CELL REPORTS
Volume 35, Issue 4, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.109031
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Funding
- Global Frontier Project of the National Research Foundation (NRF) - Ministry of Science and ICT (MSIT) of Korea [NRF-M3A6A42010-0029785, 2013M3A6A4044795]
- Yonsei University Research Fund [2020-22-0358]
- NRF grant - Korean government [2018M3A9F3055925, 2020R1A2C2005670, 2020R1I1A1A01067423, 2020R1A2C2099586, 2020M3E5E2040282]
- WISET program [2018-644]
- [NRF-2019R1I1A1A01056]
- National Research Foundation of Korea [2020R1I1A1A01067423, 2013M3A6A4044795, 2020M3E5E2040282, 2020R1A2C2099586, 2020R1A2C2005670, 2018M3A9F3055925] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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The study reveals the conformational changes of Leucyl-tRNA synthetase 1 (LARS1) upon leucine binding, providing insights into its mechanism of action in mTORC1 activation.
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 (FPYPY54)-F-50 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.
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