Comparative proteomics identifies the cell-associated lethality of M. tuberculosis RelBE-like toxin-antitoxin complexes.
Publication Type:Journal Article
Source:Structure, Volume 21, Issue 4, p.627-37 (2013)
Keywords:Amino Acid Sequence, Antitoxins, Bacterial Toxins, Catalysis, Cell Shape, Cluster Analysis, Crystallography, X-Ray, Models, Molecular, Molecular Sequence Data, Multiprotein Complexes, Mycobacterium smegmatis, Mycobacterium tuberculosis, Phylogeny, Protein Conformation, Proteomics, Sequence Alignment, Species Specificity
<p>The Mycobacterium tuberculosis (Mtb) genome encodes approximately 90 toxin-antitoxin protein complexes, including three RelBE family members, which are believed to play a major role in bacterial fitness and pathogenicity. We have determined the crystal structures of Mtb RelBE-2 and RelBE-3, and the structures reveal homologous heterotetramers. Our structures suggest RelE-2, and by extension the closely related RelE-1, use a different catalytic mechanism than RelE-3, because our analysis of the RelE-2 structure predicts additional amino acid residues that are likely to be functionally significant and are missing from analogous positions in the RelE-3 structure. Toxicity assays corroborate our structural findings; overexpression of RelE-3, whose active site is more similar to Escherichia coli YoeB, has limited consequences on bacterial growth, whereas RelE-1 and RelE-2 overexpression results in acute toxicity. Moreover, RelE-2 overexpression results in an elongated cell phenotype in Mycobacterium smegmatis and protects M. tuberculosis against antibiotics, suggesting a different functional role for RelE-2.</p>