Aminoacyl-tRNA synthetase complexes: beyond translation

Lee, Sang Won; Cho, Byeong-Hoon; Park, Sang Gyu; Kim, Sung Hoon

doi:10.1242/jcs.01342

Cited by 221 publications

(211 citation statements)

References 114 publications

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“…The complex consists of nine different ARSs and three AIMPs. Among these components, GST homology domains are found in the N-terminal appendices of two ARSs (MRS and glutamylprolyl-tRNA synthetase) and two AIMPs (AIMP2 and AIMP3) (35). Because these domains are detected only in these complex-forming ARSs and AIMPs and in the N-terminal appendix of valyl-tRNA synthetase that also forms a complex with the elongation factor (36), they are thought to be critical for the assembly of protein complexes.…”

Section: Discussionmentioning

confidence: 99%

“…Although transfection of wild-type AIMP3 enhanced the luciferase activity about 4-fold, all mutants except for the Thr 35 / Ser 40 mutant demonstrated less luciferase activity than the wild type (Fig. 5D).…”

Section: Journal Of Biological Chemistry 14037mentioning

confidence: 95%

“…Moreover, Ser 87 resides in the loop between helices ␣3 and ␣4, and Thr 35 and Ser 40 are in the extruding ␤ hairpin consisting of ␤2 and ␤3 strands. The side chain of Thr 35 faces the helix ␣2, whereas the Ser 40 side chain is exposed to solvent (Fig. 4, A and B).…”

Section: Aimp3 (Red) Has a C-terminal Domain Similar To Arc1p (Blue)mentioning

confidence: 99%

“…length MRS. Wild-type AIMP3 and mutants were prepared by in vitro translation in the presence of 35 S and mixed with the FAT domain of ATM or MRS expressed as a GST fusion protein. GST proteins were precipitated using glutathione-Sepharose, and the coprecipitation of AIMP3 mutants was followed by autoradiography.…”

Section: Journal Of Biological Chemistry 14037mentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Journal Of Biological Chemistry 14037mentioning

confidence: 95%

Section: Aimp3 (Red) Has a C-terminal Domain Similar To Arc1p (Blue)mentioning

confidence: 99%

Section: Journal Of Biological Chemistry 14037mentioning

confidence: 99%

See 2 more Smart Citations

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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“…Mouse studies have shown neuronal expression of AIMP1 in a variety of regions of the central nervous system, including the ventral horn of the spinal cord and the hippocampus. 4,5 To date, two variants for the AIMP1 gene (OMIM *603605) have been reported and these are associated with severe neurodegenerative disorder. The first alteration is a homozygous 2-bp deletion (NM_001142415.1, c.292_293delCA, p.(Gln98Valfs*30)) in exon 4 of AIMP1 that was found in six affected individuals from three related families, as well as in one single individual of another very remotely related consanguineous family of the same tribe.…”

Section: Introductionmentioning

confidence: 99%

Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration

et al. 2015

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AIMP1/p43 is a multifunctional non-catalytic component of the multisynthetase complex. The complex consists of nine catalytic and three non-catalytic proteins, which catalyze the ligation of amino acids to their cognate tRNA isoacceptors for use in protein translation. To date, two allelic variants in the AIMP1 gene have been reported as the underlying cause of autosomal recessive primary neurodegenerative disorder. Here, we present two consanguineous families from Pakistan and Iran, presenting with moderate to severe intellectual disability, global developmental delay, and speech impairment without neurodegeneration. By the combination of homozygosity mapping and next generation sequencing, we identified two homozygous missense variants, p. (Gly299Arg) and p.(Val176Gly), in the gene AIMP1 that co-segregated with the phenotype in the respective families. Molecular modeling of the variants revealed deleterious effects on the protein structure that are predicted to result in reduced AIMP1 function. Our findings indicate that the clinical spectrum for AIMP1 defects is broader than witnessed so far.

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Mutations in RARS cause hypomyelination

Wolf

Salomons

Rodenburg

et al. 2014

Annals of Neurology

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Hypomyelinating disorders of the central nervous system are still a diagnostic challenge, as many patients remain without genetic diagnosis. Using magnetic resonance imaging (MRI) pattern recognition and whole exome sequencing, we could ascertain compound heterozygous mutations in RARS in 4 patients with hypomyelination. Clinical features included severe spasticity and nystagmus. RARS encodes the cytoplasmic arginyl-tRNA synthetase, an enzyme essential for RNA translation. This protein is among the subunits of the multisynthetase complex, which emerges as a key player in myelination.

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Aminoacyl-tRNA synthetase complexes: beyond translation

Cited by 221 publications

References 114 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

Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration

Mutations in RARS cause hypomyelination

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