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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

Classification of mutations based on structural predictions. The lines between mutation categories connect the compound heterozygous mutations identified in individual cardiomyopathy patients (with red lines), and leukodystrophy patients (with blue lines). The three categories at the top are predicted to have a severe effect on the aminoacylation function of the synthetase, whereas the mutations in the lower category are predicted to retain partial catalytic activity.
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Figure 8: Classification of mutations based on structural predictions. The lines between mutation categories connect the compound heterozygous mutations identified in individual cardiomyopathy patients (with red lines), and leukodystrophy patients (with blue lines). The three categories at the top are predicted to have a severe effect on the aminoacylation function of the synthetase, whereas the mutations in the lower category are predicted to retain partial catalytic activity.

Mentions: In conclusion, our analysis of the homology model predicts that the missense mutations in the first two categories, affecting overall structure and substrate binding, severely compromise the aminoacylation by the synthetase, which is also true for the truncating mutations, whereas the missense mutations in the third category result in reduced function but with some retained aminoacylation activity. Combining the data of the compound heterozygous mutations in each patient clearly shows that all patients with leukodystrophy have combinations where one allele is in one of the two severe categories or is a truncating mutation and the other allele is in the third, moderate category, whereas all mutations of the cardiomyopathy patients are severe (Figure 8).


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)

Classification of mutations based on structural predictions. The lines between mutation categories connect the compound heterozygous mutations identified in individual cardiomyopathy patients (with red lines), and leukodystrophy patients (with blue lines). The three categories at the top are predicted to have a severe effect on the aminoacylation function of the synthetase, whereas the mutations in the lower category are predicted to retain partial catalytic activity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: Classification of mutations based on structural predictions. The lines between mutation categories connect the compound heterozygous mutations identified in individual cardiomyopathy patients (with red lines), and leukodystrophy patients (with blue lines). The three categories at the top are predicted to have a severe effect on the aminoacylation function of the synthetase, whereas the mutations in the lower category are predicted to retain partial catalytic activity.
Mentions: In conclusion, our analysis of the homology model predicts that the missense mutations in the first two categories, affecting overall structure and substrate binding, severely compromise the aminoacylation by the synthetase, which is also true for the truncating mutations, whereas the missense mutations in the third category result in reduced function but with some retained aminoacylation activity. Combining the data of the compound heterozygous mutations in each patient clearly shows that all patients with leukodystrophy have combinations where one allele is in one of the two severe categories or is a truncating mutation and the other allele is in the third, moderate category, whereas all mutations of the cardiomyopathy patients are severe (Figure 8).

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