9W01

Cryo-EM structure of LARS1:IARS1 complex

Summary for 9W01

• Entry DOI: 10.2210/pdb9w01/pdb
• EMDB information: 65488
• Descriptor: Leucine--tRNA ligase, cytoplasmic, Isoleucine--tRNA ligase, cytoplasmic (2 entities in total)
• Functional Keywords: aminoacyl-trna synthetase, complex, translation
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 279373.47

Authors

Kim, Y.,Kim, J.C.,Kim, D.W.,Kim, J.,Lee, J.,Kim, S.,Kang, J.Y.,Park, H.S. (deposition date: 2025-07-23, release date: 2026-07-29)

Primary citation

Kim, Y.,Kim, J.C.,Kim, D.W.,Kim, J.,Choi, J.,Park, S.Y.,Lee, J.,Yoon, I.,Kim, S.,Kang, J.Y.,Park, H.S.
Cryo-EM structure of the LARS1:IARS1 complex reveals a nutrient-responsive switch controlling mTORC1 signaling.
Nat Commun, 2026

PubMed Abstract: 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.

PubMed: 42276995
DOI: 10.1038/s41467-026-74085-x

Experimental method

ELECTRON MICROSCOPY (3.16 Å)