Cryo-EM structure of the LARS1:IARS1 complex reveals a nutrient-responsive switch controlling mTORC1 signaling

Aminoacyl-tRNA synthetases (ARSs) assemble into the multi-tRNA synthetase complex (MSC) to mediate noncanonical functions in cell signaling and stress responses. Among them, human cytosolic leucyl-tRNA synthetase 1 (LARS1) plays a central role in sensing leucine and activating mTORC1, thereby linking nutrient availability to metabolic regulation. Despite recent progress, fundamental questions remain unresolved about the regulatory mechanisms governing LARS1’s non-canonical functions, particularly its structural organization within the MSC. Here, we employ an integrated approach combining structural, biochemical, and cellular analyses to investigate the noncanonical roles of LARS1. The cryo-EM structure of the LARS1:isoleucyl-tRNA synthetase 1 (IARS1) complex reveals that LARS1 binds to IARS1, its anchoring partner in the MSC, via its UNE-L domain. Amino acid stimulation induces LARS1 phosphorylation at Ser1070, Ser1077, and Ser1082, which are located at the interface with IARS1. These modifications disrupt the interaction, promote LARS1 dissociation from the MSC, and enable mTORC1 activation. This study highlights phosphorylation as a conserved and critical molecular switch that orchestrates the non-canonical functions of MSC by dynamically modulating the assembly and activity of its components in response to external stimuli. Human LARS1 senses leucine to activate mTORC1, but its dissociation mechanism from the MSC remains unclear. Here the authors determine the cryo-EM structure of the LARS1–IARS1 complex, revealing phosphorylation as a switch regulating LARS1 dissociation and mTORC1 activation.