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J. Biol. Chem., Vol. 283, Issue 20, 14032-14040, May 16, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/20/14032    most recent M800859200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kim, K.-J. Articles by Kang, B. S. PubMed PubMed Citation Articles by Kim, K.-J. Articles by Kang, B. S.

Determination of Three-dimensional Structure and Residues of the Novel Tumor Suppressor AIMP3/p18 Required for the Interaction with ATM^*

Kyung-Jin Kim¹, Min Chul Park¹, So Jung Choi, Young Sun Oh, Eung-Chil Choi, Hyo Je Cho^¶, Myung Hee Kim^||, Soo-Hyun Kim^**, Dong Wook Kim^**, Sunghoon Kim², and Beom Sik Kang^¶3

From the Pohang Accelerator Laboratory, Pohang University of Science and Technology, Pohang 790-784, Korea, the Center for Medicinal Protein Network and Systems Biology, College of Pharmacy, Seoul National University, Seoul 151-742, Korea, the ^||Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea, the ^**Division of Hematology, St. Mary's Hospital College of Medicine, The Catholic University of Korea, Seoul 150-713, Korea, and the ^¶School of Life Science and Biotechnology, Kyungpook National University, Daegu 702-701, Korea

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, EF1B, 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.

Received for publication, February 1, 2008 , and in revised form, March 11, 2008.

The atomic coordinates and structure factors (code 2UZ8) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by the 21C Frontier Microbial Genomics and Application Center Program, Korea Science and Engineering Foundation Grant R17-2007-020-01000-0 from the Ministry of Science and Technology, and Basic Research Program Grant R21-2007-000-10041-0 from the Science and Engineering Foundation, Republic of Korea. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1-3.

¹ Both authors equally contributed to this work.

² To whom correspondence may be addressed: Seoul National University, Kwanak-ro 599, Kwanak-gu, Seoul 151-742, Korea. Tel.: 822-880-8180; Fax: 822-875-2621; E-mail: sungkim{at}snu.ac.kr.

³ To whom correspondence may be addressed: Kyungpook National University, Sankyeong-dong 1370, Buk-gu, Daegu 702-701, Korea. Tel.: 82-53-950-6357; E-mail: bskang2{at}knu.ac.kr.