Determination of three-dimensional structure and residues of the novel tumor suppressor AIMP3/p18 required for the interaction with ATM

Kyung Jin Kim, Chul Park Min, Jung Choi So, Sun Oh Young, Eung Chil Choi, Je Cho Hyo, Hee Kim Myung, Soo Hyun Kim, Wook Kim Dong, Sunghoon Kim, Sik Kang Beom

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Abstract

Although AIMP3/p18 is normally associated with the multi-tRNA synthetase complex via its specific interaction with methionyl-tRNA synthetase, it also works as a tumor suppressor by interacting with ATM, the upstream kinase of p53. To understand the molecular interactions of AIMP3 and the mechanisms involved, we determined the crystal structure of AIMP3 at 2.0-Å resolution and identified its potential sites of interaction with ATM. AIMP3 contains two distinct domains linked by a 7-amino acid (Lys57-Ser63) peptide, which contains a 310 helix. The 56-amino acid N-terminal domain consists of two helices into which three antiparallel β strands are inserted, and the 111-amino acid C-terminal domain contains a bundle of five helices (Thr64-Tyr152) followed by a coiled region (Pro153-Leu169). Structural analyses revealed homologous proteins such as yeast glutamyl-tRNA synthetase, Arc1p, EF1Bγ, and glutathione S-transferase and suggested two potential molecular binding sites. Moreover, mutations at the C-terminal putative binding site abolished the interaction between AIMP3 and ATM and the ability of AIMP3 to activate p53. Thus, this work identified the two potential molecular interaction sites of AIMP3 and determined the residues critical for its tumor-suppressive activity through the interaction with ATM.

Original languageEnglish
Pages (from-to)14032-14040
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number20
DOIs
Publication statusPublished - 2008 May 16

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Kim, K. J., Min, C. P., So, J. C., Young, S. O., Choi, E. C., Hyo, J. C., Myung, H. K., Kim, S. H., Dong, W. K., Kim, S., & Beom, S. K. (2008). Determination of three-dimensional structure and residues of the novel tumor suppressor AIMP3/p18 required for the interaction with ATM. Journal of Biological Chemistry, 283(20), 14032-14040. https://doi.org/10.1074/jbc.M800859200