Macromolecular assemblage of aminoacyl-tRNA synthetases: identification of protein-protein interactions and characterization of a core protein 1 1Edited by J. Karn

Quevillon, Sophie; Robinson, Jean-Charles; Berthonneau, Eric; Siatecka, Mirosława; Mirande, Marc

doi:10.1006/jmbi.1998.2316

Cited by 158 publications

(202 citation statements)

References 53 publications

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“…Although AIMP3 is necessary for the stability of MRS, it also functions as a positive regulator of the kinase activity of ATM (8). In addition, AIMP3 could target itself to form a homodimer, as implied by crystal packing shown in the present study and by previous yeast two-hybrid analyses (38). Nonetheless, gel filtration analysis of the purified AIMP3 showed no solid evidence of homodimer in solution (data not shown).…”

Section: Discussionsupporting

confidence: 54%

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

Kim

Park

Choi

et al. 2008

Journal of Biological Chemistry

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Although AIMP3/p18 is normally associated with the multitRNA 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 (Lys 57 -Ser 63 ) peptide, which contains a 3 10 helix. The 56-amino acid N-terminal domain consists of two helices into which three antiparallel ␤ strands are inserted, and the 111-amino acid C-terminal domain contains a bundle of five helices (Thr 64 -Tyr 152 ) followed by a coiled region (Pro 153 -Leu 169 ). 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.Although aminoacyl-tRNA synthetases (ARSs) 4 catalyze the ligation of specific amino acids to their cognate tRNAs, they are multifunctional proteins that are involved in the regulation of diverse signal pathways (1). Several ARSs of higher eukaryotes form an intriguing macromolecular protein complex with three non-enzymatic factors, designated AIMPs (ARS-interacting multifunctional proteins), which are also multiply involved in various biological processes. Of these factors, AIMP1/p43 is secreted as a cytokine that functions in immune response (2, 3), angiogenesis (4), and wound-healing processes (5) and also as a hormone that regulates glucose metabolism (6). AIMP2/p38 has been shown to mediate transforming growth factor-␤ signaling for c-Myc down-regulation (7). AIMP3/p18 binds to the multi-ARS complex by specifically interacting with methionyltRNA synthetase (MRS) and is translocated to the nucleus to activate p53 through the interaction with kinases such as ATM (ataxia telangiectasia mutated) and ATR (ATM-and Rad3-related) in response to DNA damage (8) or oncogenic stress (9). To understand the multifunctionality and regulation of the components of the multi-ARS complex, it is important to determine the three-dimensional structures of the components as well as the whole complex. So far, only the three-dimensional structures of the partial domains of the complex-forming ARSs such as glutamylprolyl-tRNA synthetase (10, 11), aspartyltRNA synthetase (12), and AIMP1/p43 (13, 14) have been elucidated. Here, we report the crystal structure of full-length AIMP3 and the residues and location required for the interaction with ATM. EXPERIMENTAL PROCEDURESCloning, Expression, and Purification of Human AIMP3-The cDN...

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Section: Discussionsupporting

confidence: 54%

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

Kim

Park

Choi

et al. 2008

Journal of Biological Chemistry

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“…mRNA translational rates are dependent on the activity and integrity of the multi-tRNA synthetase complex (MSC), a multiprotein complex of aminoacyl-tRNA synthetases (AARSs) and accessory proteins including AIMP1, AIMP2, and AIMP3 (AARS complex-interacting multifunctional proteins 1, 2, and 3, respectively) (17). AARS tether free amino acids to their cognate tRNAs in a process known as tRNA charging.…”

Section: Resultsmentioning

confidence: 99%

Role for the obesity-related FTO gene in the cellular sensing of amino acids

Gulati

Cheung

Antrobus

et al. 2013

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

158

147

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SNPs in the first intron of FTO (fat mass and obesity associated) are strongly associated with human obesity. While it is not yet formally established that this effect is mediated through the actions of the FTO protein itself, loss of function mutations in FTO or its murine homologue Fto result in severe growth retardation, and mice globally overexpressing FTO are obese. The mechanisms through which FTO influences growth and body composition are unknown. We describe a role for FTO in the coupling of amino acid levels to mammalian target of rapamycin complex 1 signaling. These findings suggest that FTO may influence body composition through playing a role in cellular nutrient sensing.genetics | translation | tRNA synthetase | demethylase I n 2007, single nucleotide polymorphisms (SNPs) in the first intron of fat mass and obesity related (FTO) were found to be powerfully associated with body mass index and predisposing to childhood and adult obesity (1). Many subsequent studies, covering multiple populations of European, African, and Asian ancestries, across different age ranges, have confirmed the association of FTO with body mass index (reviewed in ref.2). It is clear from the weight of evidence that the major effect of SNPs in FTO is on increased energy intake, with reduction in satiety (3-8). To date, no conclusive link has been made between the risk alleles and expression or function of FTO. However, transgenic manipulation in mice supports the notion that FTO itself regulates body weight, with overexpression resulting in obesity (9), whereas Fto-null mice (10) and humans homozygous for a loss-of-function allele (11) display postnatal growth retardation and have high rates of early mortality.FTO is widely expressed across multiple tissues, although it is most highly expressed in the brain, especially in the hypothalamus, a region that plays a key role in the control of energy homeostasis (12). We have found that expression of FTO, specifically in the arcuate nucleus of the hypothalamus, is bidirectionally regulated as a function of nutritional status-decreasing following a 48-h fast and increasing after 10 wk of exposure to a high-fat diet-and that modulating FTO levels specifically in the arcuate nucleus can influence food intake (13). Carriers of the obesity predisposing allele are hyperphagic and show altered macronutrient preference.FTO shares sequence motifs with Fe(II)-and 2-oxoglutaratedependent oxygenases (12). In vitro, recombinant FTO is able to catalyze the Fe(II)-and 2-oxoglutarate-dependent demethylation of nucleic acids. It is more active at RNA than DNA (12,14) and is capable of demethylating N6-methyladenosine (15) (more prevalent on mRNAs) or 3-methyluracil (15) (more prevalent in tRNAs and ribosomal RNAs). To date, however, there has been no understanding of how FTO might functionally link to energy homeostasis, growth, or nutrient sensing. ResultsOne of the most striking features of mice lacking FTO (10), or humans homozygous for an enzymatically inactive mutated FTO (11), is severe growth ...

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“…Although two different ARSs (tyrosyl-tRNA synthetase and WRS) and one ARS-associating factor, p43, have been reported to work as cytokines, it is not understood yet how their secretion is controlled. KRS lacks a typical signal peptide for secretion and is tightly associated with a factor, p38͞JTV-1, within the multi-ARS complex in cytosol (18,41). Because TNF-␣ induced the secretion but not the transcription of KRS, the preexisting KRS may be mobilized by TNF-␣ signal, perhaps through its posttranslational modification.…”

Section: Discussionmentioning

confidence: 99%

Human lysyl-tRNA synthetase is secreted to trigger proinflammatory response

Park

Kim

Min

et al. 2005

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

158

144

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Although aminoacyl-tRNA synthetases (ARSs) are essential for protein synthesis, they also function as regulators and signaling molecules in diverse biological processes. Here, we screened 11 different human ARSs to identify the enzyme that is secreted as a signaling molecule. Among them, we found that lysyl-tRNA synthetase (KRS) was secreted from intact human cells, and its secretion was induced by TNF-␣. The secreted KRS bound to macrophages and peripheral blood mononuclear cells to enhance the TNF-␣ production and their migration. The mitogen-activated protein kinases, extracellular signal-regulated kinase and p38 mitogen-activated protein kinase, and G␣i were determined to be involved in the signal transduction triggered by KRS. All of these activities demonstrate that human KRS may work as a previously uncharacterized signaling molecule, inducing immune response through the activation of monocyte͞macrophages.aminoacyl-tRNA synthetase ͉ cytokine ͉ TNF-␣ ͉ immune response ͉ cell migration

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Macromolecular assemblage of aminoacyl-tRNA synthetases: identification of protein-protein interactions and characterization of a core protein 1 1Edited by J. Karn

Cited by 158 publications

References 53 publications

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

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

Role for the obesity-related FTO gene in the cellular sensing of amino acids

Human lysyl-tRNA synthetase is secreted to trigger proinflammatory response

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