Structural Switch of Lysyl-tRNA Synthetase between Translation and Transcription

Yifat Ofir-Birin, Pengfei Fang, Steven P. Bennett, Hui Min Zhang, Jing Wang, Inbal Rachmin, Ryan Shapiro, Jing Song, Arie Dagan, Jorge Pozo, Sunghoon Kim, Alan G. Marshall, Paul Schimmel, Xiang Lei Yang, Hovav Nechushtan, Ehud Razin, Min Guo

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77 Citations (Scopus)

Abstract

Lysyl-tRNA synthetase (LysRS), a component of the translation apparatus, is released from the cytoplasmic multi-tRNA synthetase complex (MSC) to activate the transcription factor MITF in stimulated mast cells through undefined mechanisms. Here we show that Ser207 phosphorylation provokes a new conformer of LysRS that inactivates its translational function but activates its transcriptional function. The crystal structure of an MSC subcomplex established that LysRS is held in the MSC by binding to the N terminus of the scaffold protein p38/AIMP2. Phosphorylation-created steric clashes at the LysRS domain interface disrupt its binding grooves for p38/AIMP2, releasing LysRS and provoking its nuclear translocation. This alteration also exposes the C-terminal domain of LysRS to bind to MITF and triggers LysRS-directed production of the second messenger Ap4A that activates MITF. Thus our results establish that a single conformational change triggered by phosphorylation leads to multiple effects driving an exclusive switch of LysRS function from translation to transcription.

Original languageEnglish
Pages (from-to)30-42
Number of pages13
JournalMolecular Cell
Volume49
Issue number1
DOIs
Publication statusPublished - 2013 Jan 10

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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    Ofir-Birin, Y., Fang, P., Bennett, S. P., Zhang, H. M., Wang, J., Rachmin, I., Shapiro, R., Song, J., Dagan, A., Pozo, J., Kim, S., Marshall, A. G., Schimmel, P., Yang, X. L., Nechushtan, H., Razin, E., & Guo, M. (2013). Structural Switch of Lysyl-tRNA Synthetase between Translation and Transcription. Molecular Cell, 49(1), 30-42. https://doi.org/10.1016/j.molcel.2012.10.010