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Literature summary for 6.1.1.7 extracted from

  • Euro, L.; Konovalova, S.; Asin-Cayuela, J.; Tulinius, M.; Griffin, H.; Horvath, R.; Taylor, R.W.; Chinnery, P.F.; Schara, U.; Thorburn, D.R.; Suomalainen, A.; Chihade, J.; Tyynismaa, H.
    Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation (2015), Front. Genet., 6, 21 .
    View publication on PubMedView publication on EuropePMC

Protein Variants

Protein Variants Comment Organism
A77V naturally occuring mutation of a catalytic residue. the mutant likely affects alanine binding resulting in either totally inactive enzyme or with little aminoacylation activity due to decreased affinity to alanine Homo sapiens
E405K naturally occuring mutation of a structural residue within the tRNA recognition subdomain of the aminoacylation domain, the mutation leads to a partly reduced rate of tRNA aminoacylation due to structural instability in the tRNA recognition fold Homo sapiens
F50C naturally occuring mutation, leads to reduced rate of aminoacylation due to instability of alanine- and ATP-binding sites and impaired alanyl-adenylate formation Homo sapiens
G965R naturally occuring mutation predicted to impair protein folding and stability resulting in loss of aminoacylation activity Homo sapiens
additional information patient haplotypes around the AARS2 mutation, some patients show heterozygous mutations R592W/L155R, R592W/R329H, R592W/A961V, R592W/C218L, or R592W/Y539C, but the same pehnotype as homozygous R592W mutants. Mapping and function predictions of AARS2 mutations associated with cardiomyopathy and leukodystrophy Homo sapiens
R199C naturally occuring mutation of a catalytic residue involved in ATP binding, the mutantion leads to reduced rate of tRNA aminoacylation due to affected ATP-binding and impaired alanyl-adenylate formation Homo sapiens
R592W a naturally occuring lethal mutation in the editing domain of AARS2 causing a cardiomyopathy phenotype, homology modeling of the AARS2 missense mutant, overview. The AARS2 cardiomyopathy mutation R592W is a common founder mutation and carried by all the identified patients with the severe infantile-onset phenotype Homo sapiens
R592W/A961V naturally occuring lethal mutation R592W in gene AARS2 causing infantile cardiomyopathy, mutation A961V is predicted to impair protein folding and stability resulting in loss of aminoacylation activity Homo sapiens
R592W/C218L naturally occuring lethal mutation R592W in gene AARS2 causing infantile cardiomyopathy, truncated mutant Homo sapiens
R592W/L155R naturally occuring lethal mutation R592W in gene AARS2 causing infantile cardiomyopathy, mutation L155R is predicted to impair protein folding and stability resulting in loss of aminoacylation activity Homo sapiens
R592W/R329H naturally occuring lethal mutation R592W in gene AARS2 causing infantile cardiomyopathy, mutation R329H is predicted to impair protein folding and stability resulting in loss of aminoacylation activity Homo sapiens
R592W/Y539C naturally occuring lethal mutation R592W in gene AARS2 causing infantile cardiomyopathy. The Y539C mutation causes a dramatic decrease of aminoacylation rate due to impaired tRNA binding and positioning of the 3'-end within the active site Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
mitochondrion
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Homo sapiens 5739
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Organism

Organism UniProt Comment Textmining
Homo sapiens Q5JTZ9
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-

Synonyms

Synonyms Comment Organism
AARS2
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Homo sapiens
mitochondrial alanyl-tRNA synthetase
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Homo sapiens
mtAlaRS
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Homo sapiens

General Information

General Information Comment Organism
malfunction importance of the mtARS proteins for mitochondrial pathophysiology since nearly every nuclear gene for mtARS (out of 19) is recognized as a disease gene for mitochondrial disease. Mutations in the AARS2 gene for mitochondrial alanyl-tRNA synthetase (mtAlaRS) is observed both in patients with infantile-onset cardiomyopathy and in patients with childhood to adulthood-onset leukoencephalopathy. 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. All mutations reduce the aminoacylation activity of the synthetase, because all mtAlaRS domains contribute to tRNA binding for aminoacylation. The cardiomyopathy mutations severely compromise aminoacylation whereas partial activity is retained by the mutation combinations found in the leukodystrophy patients. Molecular basis of the distinct tissue-specific phenotypic outcomes of enzyme mutantions, structure analysis and homology modeling, overview Homo sapiens
additional information enzyme structure modeling, analysis of the contact surface between linker safety belt, and beta-barrel of the editing domain in modeled human mitochondrial AlaRS, overview Homo sapiens
physiological function 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 mitochondrial alanyl-tRNA synthetase (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 within correct amino acids Homo sapiens