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

• DOI: 10.1016/j.celrep.2021.109031
• Publication Date: 2021-04-27T16:20:36Z
• Authors: 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
• Keywords: Conformational change

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