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

J Biol Chem. 2008 May 16;283(20):14032-40. doi: 10.1074/jbc.M800859200. Epub 2008 Mar 14.

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-angstroms 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 3(10) helix. The 56-amino acid N-terminal domain consists of two helices into which three antiparallel beta 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, EF1Bgamma, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / chemistry*
  • Cloning, Molecular
  • DNA-Binding Proteins / chemistry*
  • Glutathione Transferase / metabolism
  • Humans
  • Models, Biological
  • Molecular Conformation
  • Molecular Sequence Data
  • Mutation
  • Peptide Elongation Factors / chemistry
  • Peptide Elongation Factors / physiology*
  • Protein Conformation
  • Protein Serine-Threonine Kinases / chemistry*
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / chemistry*
  • Tumor Suppressor Proteins / physiology

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • EEF1E1 protein, human
  • Peptide Elongation Factors
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Glutathione Transferase
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases

Associated data

  • PDB/2UZ8