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Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation.

Euro L, Konovalova S, Asin-Cayuela J, Tulinius M, Griffin H, Horvath R, Taylor RW, Chinnery PF, Schara U, Thorburn DR, Suomalainen A, Chihade J, Tyynismaa H - Front Genet (2015)

Bottom Line: Nevertheless, our structural analysis predicts that all mutations reduce the aminoacylation activity of the synthetase, because all mtAlaRS domains contribute to tRNA binding for aminoacylation.According to our model, the cardiomyopathy mutations severely compromise aminoacylation whereas partial activity is retained by the mutation combinations found in the leukodystrophy patients.These predictions provide a hypothesis for the molecular basis of the distinct tissue-specific phenotypic outcomes.

View Article: PubMed Central - PubMed

Affiliation: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki Helsinki, Finland.

ABSTRACT
The accuracy of mitochondrial protein synthesis is dependent on the coordinated action of nuclear-encoded mitochondrial aminoacyl-tRNA synthetases (mtARSs) and the mitochondrial DNA-encoded tRNAs. The recent advances in whole-exome sequencing have revealed the importance of the mtARS proteins for mitochondrial pathophysiology since nearly every nuclear gene for mtARS (out of 19) is now recognized as a disease gene for mitochondrial disease. Typically, defects in each mtARS have been identified in one tissue-specific disease, most commonly affecting the brain, or in one syndrome. However, mutations in the AARS2 gene for mitochondrial alanyl-tRNA synthetase (mtAlaRS) have been reported both in patients with infantile-onset cardiomyopathy and in patients with childhood to adulthood-onset leukoencephalopathy. We present here an investigation of the effects of the described mutations on the structure of the synthetase, in an effort to understand the tissue-specific outcomes of the different mutations. The mtAlaRS differs from the other mtARSs because in addition to the aminoacylation domain, it has a conserved editing domain for deacylating tRNAs that have been mischarged with incorrect amino acids. We show that the cardiomyopathy phenotype results from a single allele, causing an amino acid change R592W in the editing domain of AARS2, whereas the leukodystrophy mutations are located in other domains of the synthetase. Nevertheless, our structural analysis predicts that all mutations reduce the aminoacylation activity of the synthetase, because all mtAlaRS domains contribute to tRNA binding for aminoacylation. According to our model, the cardiomyopathy mutations severely compromise aminoacylation whereas partial activity is retained by the mutation combinations found in the leukodystrophy patients. These predictions provide a hypothesis for the molecular basis of the distinct tissue-specific phenotypic outcomes.

No MeSH data available.


Related in: MedlinePlus

Patient haplotypes around the AARS2 mutation. The haplotype of the Swedish patient shows recombination 165 kilobases upstream of the mutation site.
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Figure 1: Patient haplotypes around the AARS2 mutation. The haplotype of the Swedish patient shows recombination 165 kilobases upstream of the mutation site.

Mentions: Patients with British or German origin were recently suggested to share a common disease haplotype for R592W (Taylor et al., 2014). We present here the haplotypes surrounding this mutation for patients from Finland, Sweden, and Australia in comparison to the British and German patients, which suggest that the shared mutation described in each AARS2 cardiomyopathy patient originates from a common founder (Figure 1).


Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation.

Euro L, Konovalova S, Asin-Cayuela J, Tulinius M, Griffin H, Horvath R, Taylor RW, Chinnery PF, Schara U, Thorburn DR, Suomalainen A, Chihade J, Tyynismaa H - Front Genet (2015)

Patient haplotypes around the AARS2 mutation. The haplotype of the Swedish patient shows recombination 165 kilobases upstream of the mutation site.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4319469&req=5

Figure 1: Patient haplotypes around the AARS2 mutation. The haplotype of the Swedish patient shows recombination 165 kilobases upstream of the mutation site.
Mentions: Patients with British or German origin were recently suggested to share a common disease haplotype for R592W (Taylor et al., 2014). We present here the haplotypes surrounding this mutation for patients from Finland, Sweden, and Australia in comparison to the British and German patients, which suggest that the shared mutation described in each AARS2 cardiomyopathy patient originates from a common founder (Figure 1).

Bottom Line: Nevertheless, our structural analysis predicts that all mutations reduce the aminoacylation activity of the synthetase, because all mtAlaRS domains contribute to tRNA binding for aminoacylation.According to our model, the cardiomyopathy mutations severely compromise aminoacylation whereas partial activity is retained by the mutation combinations found in the leukodystrophy patients.These predictions provide a hypothesis for the molecular basis of the distinct tissue-specific phenotypic outcomes.

View Article: PubMed Central - PubMed

Affiliation: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki Helsinki, Finland.

ABSTRACT
The accuracy of mitochondrial protein synthesis is dependent on the coordinated action of nuclear-encoded mitochondrial aminoacyl-tRNA synthetases (mtARSs) and the mitochondrial DNA-encoded tRNAs. The recent advances in whole-exome sequencing have revealed the importance of the mtARS proteins for mitochondrial pathophysiology since nearly every nuclear gene for mtARS (out of 19) is now recognized as a disease gene for mitochondrial disease. Typically, defects in each mtARS have been identified in one tissue-specific disease, most commonly affecting the brain, or in one syndrome. However, mutations in the AARS2 gene for mitochondrial alanyl-tRNA synthetase (mtAlaRS) have been reported both in patients with infantile-onset cardiomyopathy and in patients with childhood to adulthood-onset leukoencephalopathy. We present here an investigation of the effects of the described mutations on the structure of the synthetase, in an effort to understand the tissue-specific outcomes of the different mutations. The mtAlaRS differs from the other mtARSs because in addition to the aminoacylation domain, it has a conserved editing domain for deacylating tRNAs that have been mischarged with incorrect amino acids. We show that the cardiomyopathy phenotype results from a single allele, causing an amino acid change R592W in the editing domain of AARS2, whereas the leukodystrophy mutations are located in other domains of the synthetase. Nevertheless, our structural analysis predicts that all mutations reduce the aminoacylation activity of the synthetase, because all mtAlaRS domains contribute to tRNA binding for aminoacylation. According to our model, the cardiomyopathy mutations severely compromise aminoacylation whereas partial activity is retained by the mutation combinations found in the leukodystrophy patients. These predictions provide a hypothesis for the molecular basis of the distinct tissue-specific phenotypic outcomes.

No MeSH data available.


Related in: MedlinePlus