Figure 1. Cryo-EM structure of the LARS1:IARS1 complex. (a) Domain organization of human LARS1 and IARS1. Regions not resolved in the cryo-EM map are indicated with white dotted boxes. CD, catalytic domain; CP, connective peptide; SC-fold, stem contact fold; ABD, anticodon-binding domain; UNE-L/UNE-I, domains unique appended to LARS1 and IARS1, respectively. (b) Cryo-EM map of the LARS1:IARS1 complex. Each domain is colored as in (a), and the overall architecture of the complex is shown from two orientations related by a 180° rotation. Credit KAIST

Published in Nature Communications, the study reveals how amino acid availability triggers the release of a key protein from the multi-tRNA synthetase complex (MSC) to activate mTORC1, a master regulator of cell growth.

Led by Professors Hee-Sung Park and Jin Young Kang from KAIST alongside Professor Sunghoon Kim from Yonsei University, the discovery identifies a potential target for next-generation anticancer therapies.

Cells continuously monitor environmental nutrient levels, particularly amino acids, to regulate protein synthesis and metabolism. Central to this regulation is mammalian Target of Rapamycin Complex 1 (mTORC1), which acts as a cellular growth switch.

When nutrients are abundant, mTORC1 promotes cell division and growth. However, hyperactivation of mTORC1 causes unconstrained cell proliferation, a hallmark of many human cancers. While direct mTORC1 inhibitors exist, they often disrupt normal cell functions because healthy cells also rely on mTORC1 for basic metabolism.

The research team focused on the multi-tRNA synthetase complex (MSC), a large protein assembly involved in protein synthesis. They discovered that the enzyme leucyl-tRNA synthetase 1 (LARS1), which attaches leucine to tRNA and serves as an intracellular leucine sensor, functions as the primary messenger:

• Nutrient scarcity:
  • LARS1 remains tightly anchored within the MSC by binding to its partner protein, IARS1. While held inside the MSC, LARS1 cannot trigger growth signals, keeping mTORC1 turned off.
• Nutrient abundance:
  • When amino acid levels rise, LARS1 undergoes phosphorylation, gaining chemical tags that weaken its binding interface with IARS1.
• Switch activation:
  • The phosphorylated LARS1 detaches from the MSC and translocates to activate mTORC1, turning on cell growth processes.

Using near-atomic resolution cryo-electron microscopy (cryo-EM), the researchers captured three-dimensional structural maps of the LARS1:IARS1 complex. The structural analysis visually confirmed how phosphorylation at specific binding sites destabilises the interaction between LARS1 and IARS1.

To validate the mechanism, the team engineered phosphomimetic mutant proteins designed to imitate LARS1 in its permanently phosphorylated state. These variants significantly boosted mTORC1 activity, confirming that LARS1 phosphorylation acts as the direct molecular trigger converting nutrient detection into growth signalling.

By detailing how nutrient signals trigger LARS1 release, the study highlights a potential strategy to treat cancer without blocking mTORC1 directly.

Identifying and targeting the specific upstream kinase enzyme responsible for phosphorylating LARS1 could allow researchers to intercept abnormal growth signals before they reach mTORC1, reducing side effects on healthy tissues.