title: Neurodegenerative disease-associated mutants of a human mitochondrial aminoacyl-tRNA synthetase present individual molecular signatures.
abstract: Mutations in human mitochondrial aminoacyl-tRNA synthetases are associated with a variety of neurodegenerative disorders. The effects of these mutations on the structure and function of the enzymes remain to be established. Here, we investigate six mutants of the aspartyl-tRNA synthetase correlated with leukoencephalopathies. Our integrated strategy, combining an ensemble of biochemical and biophysical approaches, reveals that mutants are diversely affected with respect to their solubility in cellular extracts and stability in solution, but not in architecture. Mutations with mild effects on solubility occur in patients as allelic combinations whereas those with strong effects on solubility or on aminoacylation are necessarily associated with a partially functional allele. The fact that all mutations show individual molecular and cellular signatures and affect amino acids only conserved in mammals, points towards an alternative function besides aminoacylation.
authors.affiliation: Architecture et Réactivité de l'ARN, CNRS, Université de Strasbourg, IBMC, 15 rue René Descartes, 67084 STRASBOURG Cedex, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Sauter
authors.affiliation: Architecture et Réactivité de l'ARN, CNRS, Université de Strasbourg, IBMC, 15 rue René Descartes, 67084 STRASBOURG Cedex, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Lorber
authors.affiliation: Architecture et Réactivité de l'ARN, CNRS, Université de Strasbourg, IBMC, 15 rue René Descartes, 67084 STRASBOURG Cedex, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Gaudry
authors.affiliation: Architecture et Réactivité de l'ARN, CNRS, Université de Strasbourg, IBMC, 15 rue René Descartes, 67084 STRASBOURG Cedex, France.
authors.forename: Loukmane
authors.initials: L
authors.lastname: Karim
authors.affiliation: Architecture et Réactivité de l'ARN, CNRS, Université de Strasbourg, IBMC, 15 rue René Descartes, 67084 STRASBOURG Cedex, France.
authors.forename: Hagen
authors.initials: H
authors.lastname: Schwenzer
authors.affiliation: Synchrotron SOLEIL, L'Orme des Merisiers Saint Aubin, 91410 Gif-sur-Yvette, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Wien
authors.affiliation: Synchrotron SOLEIL, L'Orme des Merisiers Saint Aubin, 91410 Gif-sur-Yvette, France.|URBIA-Nantes, INRA Centre de Nantes, 60 rue de la Géraudière, 44316 Nantes, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Roblin
authors.affiliation: Architecture et Réactivité de l'ARN, CNRS, Université de Strasbourg, IBMC, 15 rue René Descartes, 67084 STRASBOURG Cedex, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Florentz
authors.affiliation: Architecture et Réactivité de l'ARN, CNRS, Université de Strasbourg, IBMC, 15 rue René Descartes, 67084 STRASBOURG Cedex, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Sissler
mesh_terms: D000818:Animals; D001226:Aspartate-tRNA Ligase / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D004795:Enzyme Stability / Q000235:genetics; D006801:Humans; D056784:Leukoencephalopathies / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation
chemical_list: D024101:Mitochondrial Proteins; D001226:Aspartate-tRNA Ligase