title: Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation.
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.
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki Helsinki, Finland.
authors.forename: Liliya
authors.initials: L
authors.lastname: Euro
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki Helsinki, Finland.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Konovalova
authors.affiliation: Department of Clinical Chemistry, University of Gothenburg, Sahlgrenska University Hospital Gothenburg, Sweden.
authors.forename: Jorge
authors.initials: J
authors.lastname: Asin-Cayuela
authors.affiliation: Department of Pediatrics, Queen Silvia Children's Hospital, University of Gothenburg Gothenburg, Sweden.
authors.forename: Már
authors.initials: M
authors.lastname: Tulinius
authors.affiliation: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University Newcastle upon Tyne, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Griffin
authors.affiliation: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University Newcastle upon Tyne, UK.
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.affiliation: Institute of Neuroscience, Wellcome Trust Centre for Mitochondrial Research, Newcastle University Newcastle upon Tyne, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University Newcastle upon Tyne, UK.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.affiliation: Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, University of Essen Essen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schara
authors.affiliation: Murdoch Childrens Research Institute, Royal Childrens Hospital and Department of Paediatrics, University of Melbourne Melbourne, VIC, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki Helsinki, Finland ; Department of Neurology, Helsinki University Central Hospital Helsinki, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
authors.affiliation: Department of Chemistry, Carleton College Northfield, MN, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Chihade
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki Helsinki, Finland ; Department of Medical Genetics, Haartman Institute, University of Helsinki Helsinki, Finland.
authors.forename: Henna
authors.initials: H
authors.lastname: Tyynismaa
keywords: alanyl-tRNA synthetase; aminoacyl-tRNA synthetases; mitochondrial disease; structural modeling; tissue-specificity