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

Kim, Kyungjin; Park, Min-Chul; Choi, So Jung; Oh, Yung-Hwan; Choi, Eung‐Chil; Cho, Hyo Je; Kim, Myung Hee; Kim, Soohyun; Kim, Dong Wook; Kim, Sung Hoon; Kang, Beom Sik

doi:10.1074/jbc.m800859200

Cited by 39 publications

(45 citation statements)

References 40 publications

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“…3A) (17,33). The C-terminal half of p38 has a domain with structural homology to GST (35,36), which is also found in mammalian MetRS, p18, CysRS, and ValRS, as well as in EF1β and EF1γ (35,37,38). All of these GST domains mediate protein-protein interactions (11,39,40).…”

Section: The Structure Of Tetrameric Lysrs In Solution Resembles Its mentioning

confidence: 99%

Structural context for mobilization of a human tRNA synthetase from its cytoplasmic complex

Fang

Zhang

Shapiro

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Human lysyl-tRNA synthetase is bound to the multi-tRNA synthetase complex (MSC) that maintains and regulates the aminoacylation and nuclear functions of LysRS. The p38 scaffold protein binds LysRS to the MSC and, only with the appropriate cue, mobilizes LysRS for redirection to the nucleus to interact with the microphthalmia associated transcription factor (MITF). In recent work, an ðα 2 Þ 2 LysRS tetramer crystallized to yield a high-resolution structure and raised the question of how LysRS is arranged (dimer or tetramer) in the MSC to interact with p38. To understand the structural organization of the LysRS-p38 complex that regulates LysRS mobilization, we investigated the complex by use of small angle X-ray scattering and hydrogen-deuterium exchange with mass spectrometry in solution. The structure revealed a surprising α 2 β 1 ∶β 1 α 2 organization in which a dimeric p38 scaffold holds two LysRS α 2 dimers in a parallel configuration. Each of the N-terminal 48 residues of p38 binds one LysRS dimer and, in so doing, brings two copies of the LysRS dimer into the MSC. The results suggest that this unique geometry, which reconfigures the LysRS tetramer from α 2 ∶α 2 to α 2 β 1 ∶β 1 α 2 , is designed to control both retention and mobilization of LysRS from the MSC.noncanonical function | p38/AIMP2 | structural plasticity

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Section: The Structure Of Tetrameric Lysrs In Solution Resembles Its mentioning

confidence: 99%

Structural context for mobilization of a human tRNA synthetase from its cytoplasmic complex

Fang

Zhang

Shapiro

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Within this complex, MRS forms a strong association with the tumor suppressor AIMP3 (10-12). Although AIMP3 is mainly anchored to MRS in the cytosol, it also activates ATM/ATR in the nucleus upon DNA damage or oncogenic stress (11,13,14). However, it is unclear whether nuclear AIMP3 is actually translocated from the cytosolic MSC.…”

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confidence: 99%

Dual role of methionyl-tRNA synthetase in the regulation of translation and tumor suppressor activity of aminoacyl-tRNA synthetase-interacting multifunctional protein-3

Kwon

Kang

Lee

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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110

102

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Mammalian methionyl-tRNA synthetase (MRS) plays an essential role in initiating translation by transferring Met to initiator tRNA (tRNA i Met ). MRS also provides a cytosolic anchoring site for aminoacyl-tRNA synthetase-interacting multifunctional protein-3 (AIMP3)/ p18, a potent tumor suppressor that is translocated to the nucleus for DNA repair upon DNA damage. However, the mechanism by which this enzyme mediates these two seemingly unrelated functions is unknown. Here we demonstrate that AIMP3 is released from MRS by UV irradiation-induced stress. Dissociation was induced by phosphorylation of MRS at Ser662 by general control nonrepressed-2 (GCN2) following UV irradiation. Substitution of Ser662 to Asp (S662D) induced a conformational change in MRS and significantly reduced its interaction with AIMP3. This mutant possessed significantly reduced MRS catalytic activity because of loss of tRNA Met binding, resulting in down-regulation of global translation. According to the Met incorporation assay using stable HeLa cells expressing MRS S662A or eukaryotic initiation factor-2 subunit-α (eIF2α) S51A, inactivation of GCN2-induced phosphorylation at eIF2α or MRS augmented the role of the other, suggesting a cross-talk between MRS and eIF2α for efficient translational inhibition. This work reveals a unique mode of regulation of global translation as mediated by aminoacyl-tRNA synthetase, specifically MRS, which we herein identified as a previously unidentified GCN2 substrate. In addition, our research suggests a dual role for MRS: (i) as a coregulator with eIF2α for GCN2-mediated translational inhibition; and (ii) as a coupler of translational inhibition and DNA repair following DNA damage by releasing bound tumor suppressor AIMP3 for its nuclear translocation.T ranslational regulation is a mechanism by which genetic expression can be modulated to cope with various biological conditions. In diseases such as cancer, dysregulation of protein synthesis is frequently observed; therefore, accurate translational control appears to be important for the maintenance of normal growth and proliferation (1, 2). Under stress conditions, global translational control mainly occurs at the point of translational initiation through modification of eukaryotic initiation factors (eIFs). A key regulatory mechanism of this process is phosphorylation of eIF2 subunit-α (eIF2α), which prevents formation of a ternary complex (TC) comprising eIF2, GTP, and Metcharged initiator tRNA (Met-tRNA i Met ), thereby inhibiting further rounds of translation initiation (3).Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for protein synthesis, linking codons to their corresponding amino acids (4, 5). A key factor in translation initiation, methionyltRNA synthetase (MRS) produces Met-tRNA i Met , which is indispensable for TC formation. MRS has been also found in the nucleus, where it may play a role in the biogenesis of rRNA (6). Under oxidative stress, MRS charges Met to noncognate tRNAs at a high frequency, resulting in reduced translational fi...

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“…4C). The mutations that ablate its ability to interact with ATM were found in leukemia patients (42) (Fig. 4A).…”

Section: Functional Significance Of Aimp3 For Chromosome Stability Anmentioning

confidence: 99%

“…Recent X-ray analysis of AIMP3 revealed structural homology to the proteins with GST fold such as yeast glutamyl-tRNA synthetase, Arc1p, EF-1bc, and glutathione S-transferase (42) (Fig. 4A).…”

Section: Functional Significance Of Aimp3 For Chromosome Stability Anmentioning

confidence: 99%

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Aminoacyl‐tRNA synthetase–interacting multifunctional proteins (AIMPs): A triad for cellular homeostasis

2010

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SummaryAminoacyl-tRNA synthetases (ARSs) are highly conserved for efficient and precise translation of genetic codes. In higher eukaryotic systems, several different ARSs including glutamylprolyl-, isoelucyl-, leucyl-, methionyl-, glutaminyl-, lysyl-, arginyl-, and aspartyl-tRNA synthetase form a macromolecular protein complex with three nonenzymatic cofactors (AIMP1/ p43, AIMP2/p38, and AIMP3/p18). Although the structure and functional implications for this complex formation are not completely understood, rapidly accumulating evidences suggest that this complex would work as a molecular hub linked to the multiple signaling pathways that involve the components of enzymes and cofactors. In this article, the roles of three nonenzymatic components of the multi-tRNA synthetase complex in the assembly of the components and in cell regulation are addressed.2010 IUBMB IUBMB Life, 62(4): [296][297][298][299][300][301][302] 2010

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

Cited by 39 publications

References 40 publications

Structural context for mobilization of a human tRNA synthetase from its cytoplasmic complex

Structural context for mobilization of a human tRNA synthetase from its cytoplasmic complex

Dual role of methionyl-tRNA synthetase in the regulation of translation and tumor suppressor activity of aminoacyl-tRNA synthetase-interacting multifunctional protein-3

Aminoacyl‐tRNA synthetase–interacting multifunctional proteins (AIMPs): A triad for cellular homeostasis

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