Mutations in MARS identified in a specific type of pulmonary alveolar proteinosis alter methionyl-tRNA synthetase activity.

Abstract

Biallelic missense mutations in MARS are responsible for rare but severe cases of pulmonary alveolar proteinosis (PAP) prevalent on the island of La Réunion. MARS encodes cytosolic methionyl-tRNA synthetase (MetRS), an essential translation factor. The multisystemic effects observed in patients with this form of PAP are consistent with a loss-of-function defect in an ubiquitously expressed enzyme. The pathophysiological mechanisms involved in MARS-related PAP are currently unknown. In this work, we analyzed the effect of the PAP-related mutations in MARS on the thermal stability and on the catalytic parameters of the MetRS mutants, relative to wild-type. The effect of these mutations on the structural integrity of the enzyme as a member of the cytosolic multisynthetase complex was also investigated. Our results establish that the PAP-related substitutions in MetRS impact the tRNAMet -aminoacylation reaction especially at the level of methionine recognition, and suggest a direct link between the loss of activity of the enzyme and the pathological disorders in PAP.

• Authors: Martine Comisso, Alice Hadchouel, Jacques de Blic, Marc Mirande
• Journal: The FEBS journal (FEBS J) Vol. 285 Issue 14 Pg. 2654-2661 (07 2018) ISSN: 1742-4658 [Electronic] England
• PMID: 29775242 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Federation of European Biochemical Societies.

Chemical References

• RNA, Transfer, Met
• Recombinant Proteins
• Methionine
• MARS1 protein, human
• Methionine-tRNA Ligase

Topics

• Amino Acid Sequence
• Animals
• Binding Sites
• Cloning, Molecular
• Escherichia coli (genetics, metabolism)
• Gene Expression
• Genetic Vectors (chemistry, metabolism)
• Humans
• Methionine (chemistry, metabolism)
• Methionine-tRNA Ligase (chemistry, genetics, metabolism)
• Models, Molecular
• Mutagenesis, Site-Directed
• Mutation
• Protein Binding
• Protein Conformation, alpha-Helical
• Protein Conformation, beta-Strand
• Protein Interaction Domains and Motifs
• Pulmonary Alveolar Proteinosis (genetics, metabolism, pathology)
• RNA, Transfer, Met (genetics, metabolism)
• Recombinant Proteins (chemistry, genetics, metabolism)
• Sequence Alignment
• Sequence Homology, Amino Acid
• Substrate Specificity
• Transfer RNA Aminoacylation