The DRS–AIMP2–EPRS subcomplex acts as a pivot in the multi-tRNA synthetase complex

Hahn, Hyunggu; Park, Sang Ho; Kim, Hyun Jung; Kim, Sung Hoon; Han, Byung Woo

doi:10.1107/s2052252519010790

Cited by 12 publications

(12 citation statements)

References 42 publications

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“…Previous X-ray crystallography data established a core of four GST-like domains that was not challenged by our results, and was used as a starting point in our model development ( 27 , 29 ). Our data showed AspRS cross-linked to two core constituents, namely, AIMP3 and MetRS – an unexpected result since previous biochemical and structural studies showed AspRS binding AIMP2 (Figure 1B ) ( 18 , 27 ). However, a recent report showed a 58-amino acid degradation fragment of AspRS (AspRS 336–393 ) resides in a crevice formed by AIMP2 and AIMP3 in the GST-like core ( 29 ).…”

Section: Resultssupporting

confidence: 71%

“…MSC release of GluProRS and LysRS does not adversely influence cell viability, but their effects on MSC structure have not been investigated in depth. Although AspRS has been proposed to undergo stimulus-dependent release from the MSC ( 18 ), its central position suggests release might profoundly influence MSC structure. Consistent with previous electron microscopy showing a central location of AIMP1 ( 99 ), AIMP1 in our model forms a central belt-like structure interacting with multiple AARSs suggesting that release of intact AIMP1 might be detrimental to MSC structure.…”

Section: Discussionmentioning

confidence: 99%

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3-Dimensional architecture of the human multi-tRNA synthetase complex

Khan

Baleanu-Gogonea

Willard

et al. 2020

Nucleic Acids Research

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Abstract In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). AARSs have critical roles in interpretation of the genetic code during protein synthesis, and in non-canonical functions unrelated to translation. Nonetheless, the structure and function of the MSC remain unclear. Partial or complete crystal structures of all MSC constituents have been reported; however, the structure of the holo-MSC has not been resolved. We have taken advantage of cross-linking mass spectrometry (XL-MS) and molecular docking to interrogate the three-dimensional architecture of the MSC in human HEK293T cells. The XL-MS approach uniquely provides structural information on flexibly appended domains, characteristic of nearly all MSC constituents. Using the MS-cleavable cross-linker, disuccinimidyl sulfoxide, inter-protein cross-links spanning all MSC constituents were observed, including cross-links between eight protein pairs not previously known to interact. Intra-protein cross-links defined new structural relationships between domains in several constituents. Unexpectedly, an asymmetric AARS distribution was observed featuring a clustering of tRNA anti-codon binding domains on one MSC face. Possibly, the non-uniform localization improves efficiency of delivery of charged tRNA’s to an interacting ribosome during translation. In summary, we show a highly compact, 3D structural model of the human holo-MSC.

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Section: Resultssupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

3-Dimensional architecture of the human multi-tRNA synthetase complex

Khan

Baleanu-Gogonea

Willard

et al. 2020

Nucleic Acids Research

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“…While important progress has been made on the structure of the MSC, it is still not known in full molecular detail ( 51 , 65 , 66 ). We show here that arginyl-tRNA synthetase can be excluded from the MSC by ablation of its N-terminal leucine zipper (LZ) (Figures 2 and 3 ).…”

Section: Discussionmentioning

confidence: 99%

“…It is unclear how the ArgRS LZ domain and GlnRS contribute to the nuclear distribution of the MSC, as neither contain nuclear localization sequences (NLS). Despite significant advances in our understanding of the MSC structure ( 51 , 65 , 66 ), it is yet unclear whether arrangements in the MSC could control exposure of other aaRS’s nuclear import or export cues upon ArgRS exclusion.…”

Section: Discussionmentioning

confidence: 99%

Regulation of ex-translational activities is the primary function of the multi-tRNA synthetase complex

Cui

Kapur

Diedrich

et al. 2020

Nucleic Acids Research

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During mRNA translation, tRNAs are charged by aminoacyl-tRNA synthetases and subsequently used by ribosomes. A multi-enzyme aminoacyl-tRNA synthetase complex (MSC) has been proposed to increase protein synthesis efficiency by passing charged tRNAs to ribosomes. An alternative function is that the MSC repurposes specific synthetases that are released from the MSC upon cues for functions independent of translation. To explore this, we generated mammalian cells in which arginyl-tRNA synthetase and/or glutaminyl-tRNA synthetase were absent from the MSC. Protein synthesis, under a variety of stress conditions, was unchanged. Most strikingly, levels of charged tRNAArg and tRNAGln remained unchanged and no ribosome pausing was observed at codons for arginine and glutamine. Thus, increasing or regulating protein synthesis efficiency is not dependent on arginyl-tRNA synthetase and glutaminyl-tRNA synthetase in the MSC. Alternatively, and consistent with previously reported ex-translational roles requiring changes in synthetase cellular localizations, our manipulations of the MSC visibly changed localization.

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“…[1][2][3][4] Other examples include binary or tertiary glutathione S-transferase (GST)-homology domain complexes: EPRS1 GST :AIMP2 GST , EPRS1 GST :EEF1E1, MARS1 GST :EEF1E1, and EPRS1 GST :AIMP2 GST :DARS1. 5,6 These assemblies are considered to be involved in flexible associations with each other to support subcellular translocations of EPRS1, MARS1, and EEF1E1 for their non-translational roles. [7][8][9] Other sub-interactions of the MSC are correlated with substrate tRNAs.…”

Section: Introductionmentioning

confidence: 99%