Localization and RNA Binding of Mitochondrial Aminoacyl tRNA Synthetases

Garin, Shahar; Levi, Ofri; Cohen, Bar; Golani-Armon, Adi; Arava, Yoav

doi:10.3390/genes11101185

Cited by 13 publications

(10 citation statements)

References 157 publications

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“…Therefore, we decided to investigate the capacity of Cterm to bind mt-tRNALeu (UUR) in cultured cells. In addition, we explored whether this molecule is able to interact with other mitochondrial RNA species, since it is well documented that aaRSs also have the ability to bind non-tRNA substrates [ 22 ]. We employed a MELAS cybrid line with a >95% mutation load that stably overexpressed the FLAG-tagged Cterm construct.…”

Section: Resultsmentioning

confidence: 99%

“…This circumstance is in accordance with the hypothesis that the Cterm mode of RNA recognition relies more on structural rather than on specific base–base interactions, as observed in the available 3D structures of whole LeuRS-tRNALeu complexes from bacterial species [ 45 ]. This feature is reminiscent of the promiscuous RNA binding mode typical of aaRSs [ 22 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

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Exploring the Ability of LARS2 Carboxy-Terminal Domain in Rescuing the MELAS Phenotype

Capriglia

Rizzo

Petrosillo

et al. 2021

Life

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The m.3243A>G mutation within the mitochondrial mt-tRNALeu(UUR) gene is the most prevalent variant linked to mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome. This pathogenic mutation causes severe impairment of mitochondrial protein synthesis due to alterations of the mutated tRNA, such as reduced aminoacylation and a lack of post-transcriptional modification. In transmitochondrial cybrids, overexpression of human mitochondrial leucyl-tRNA synthetase (LARS2) has proven effective in rescuing the phenotype associated with m.3243A>G substitution. The rescuing activity resides in the carboxy-terminal domain (Cterm) of the enzyme; however, the precise molecular mechanisms underlying this process have not been fully elucidated. To deepen our knowledge on the rescuing mechanisms, we demonstrated the interactions of the Cterm with mutated mt-tRNALeu(UUR) and its precursor in MELAS cybrids. Further, the effect of Cterm expression on mitochondrial functions was evaluated. We found that Cterm ameliorates de novo mitochondrial protein synthesis, whilst it has no effect on mt-tRNALeu(UUR) steady-state levels and aminoacylation. Despite the complete recovery of cell viability and the increase in mitochondrial translation, Cterm-overexpressing cybrids were not able to recover bioenergetic competence. These data suggest that, in our MELAS cell model, the beneficial effect of Cterm may be mediated by factors that are independent of the mitochondrial bioenergetics.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Exploring the Ability of LARS2 Carboxy-Terminal Domain in Rescuing the MELAS Phenotype

Capriglia

Rizzo

Petrosillo

et al. 2021

Life

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“…While we were not able to confirm the presence of mitochondrial aminoacyl-tRNA synthetases for only three amino acids (tyr, arg, trp), the set clearly lacks cytosolic aminoacyl-tRNA synthetases for at least nine amino acids (ala, gly, his, ile, leu, lys, pro, ser, val). Such bias can hardly be explained by the incompleteness of the data and it rather suggests that these enzymes are dually localised and charge tRNAs in both compartments as was already shown for many organism including Trypanosoma brucei , where this holds for an almost complete set 28 . The evolutionary history of some of the enzymes was noteworthy.…”

Section: Resultsmentioning

confidence: 90%

Heterotrophic euglenid Rhabdomonas costata resembles its phototrophic relatives in many aspects of molecular and cell biology

Soukal

Hrdá

Karnkowska

et al. 2021

Sci Rep

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Euglenids represent a group of protists with diverse modes of feeding. To date, only a partial genomic sequence of Euglena gracilis and transcriptomes of several phototrophic and secondarily osmotrophic species are available, while primarily heterotrophic euglenids are seriously undersampled. In this work, we begin to fill this gap by presenting genomic and transcriptomic drafts of a primary osmotroph, Rhabdomonas costata. The current genomic assembly length of 100 Mbp is 14× smaller than that of E. gracilis. Despite being too fragmented for comprehensive gene prediction it provided fragments of the mitochondrial genome and comparison of the transcriptomic and genomic data revealed features of its introns, including several candidates for nonconventional types. A set of 39,456 putative R. costata proteins was predicted from the transcriptome. Annotation of the mitochondrial core metabolism provides the first data on the facultatively anaerobic mitochondrion of R. costata, which in most respects resembles the mitochondrion of E. gracilis with a certain level of streamlining. R. costata can synthetise thiamine by enzymes of heterogenous provenances and haem by a mitochondrial-cytoplasmic C4 pathway with enzymes orthologous to those found in E. gracilis. The low percentage of green algae-affiliated genes supports the ancestrally osmotrophic status of this species.

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“…For instance, the P. falciparum tyrosyl-tRNA synthetase ( Pf YRS) possesses cytokine-like activity [ 25 ]. The aaRSs are mainly located in the cytoplasm and the mitochondria for protein synthesis [ 26 ]. Recently, aaRSs have also emerged as a potential drug target for several eukaryotic pathogens ( Leishmania , Plasmodium , and Toxoplasma ) via multi-site targeting [ 16 – 18 , 25 , 27 – 35 ].…”

mentioning

confidence: 99%

“…Consistent with other species such as Babesia spp., Plasmodium spp., and Homo sapiens , a larger number of aaRSs are found in the cytoplasm compared to the mitochondria [ 34 , 37 ]. Generally, mitochondrial-targeting peptide is present at the N- or C-terminus or at the internal site of the protein [ 26 ]. It is worth noting that protein/tRNA migration to the mitochondria has been reported in the absence of signal peptides [ 38 ].…”

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confidence: 99%

Drug targeting of aminoacyl-tRNA synthetases in Anopheles species and Aedes aegypti that cause malaria and dengue

2021

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Background Mosquito-borne diseases have a devastating impact on human civilization. A few species of Anopheles mosquitoes are responsible for malaria transmission, and while there has been a reduction in malaria-related deaths worldwide, growing insecticide resistance is a cause for concern. Aedes mosquitoes are known vectors of viral infections, including dengue, yellow fever, chikungunya, and Zika. Aminoacyl-tRNA synthetases (aaRSs) are key players in protein synthesis and are potent anti-infective drug targets. The structure–function activity relationship of aaRSs in mosquitoes (in particular, Anopheles and Aedes spp.) remains unexplored. Methods We employed computational techniques to identify aaRSs from five different mosquito species (Anopheles culicifacies, Anopheles stephensi, Anopheles gambiae, Anopheles minimus, and Aedes aegypti). The VectorBase database (https://vectorbase.org/vectorbase/app) and web-based tools were utilized to predict the subcellular localizations (TargetP-2.0, UniProt, DeepLoc-1.0), physicochemical characteristics (ProtParam), and domain arrangements (PfAM, InterPro) of the aaRSs. Structural models for prolyl (PRS)-, and phenylalanyl (FRS)-tRNA synthetases—were generated using the I-TASSER and Phyre protein modeling servers. Results Among the vector species, a total of 37 (An. gambiae), 37 (An. culicifacies), 37 (An. stephensi), 37 (An. minimus), and 35 (Ae. aegypti) different aaRSs were characterized within their respective mosquito genomes. Sequence identity amongst the aaRSs from the four Anopheles spp. was > 80% and in Ae. aegypti was > 50%. Conclusions Structural analysis of two important aminoacyl-tRNA synthetases [prolyl (PRS) and phenylanalyl (FRS)] of Anopheles spp. suggests structural and sequence similarity with potential antimalarial inhibitor [halofuginone (HF) and bicyclic azetidine (BRD1369)] binding sites. This suggests the potential for repurposing of these inhibitors against the studied Anopheles spp. and Ae. aegypti.

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Localization and RNA Binding of Mitochondrial Aminoacyl tRNA Synthetases

Cited by 13 publications

References 157 publications

Exploring the Ability of LARS2 Carboxy-Terminal Domain in Rescuing the MELAS Phenotype

Exploring the Ability of LARS2 Carboxy-Terminal Domain in Rescuing the MELAS Phenotype

Heterotrophic euglenid Rhabdomonas costata resembles its phototrophic relatives in many aspects of molecular and cell biology

Drug targeting of aminoacyl-tRNA synthetases in Anopheles species and Aedes aegypti that cause malaria and dengue

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