title: Comparative proteomics identifies the cell-associated lethality of M. tuberculosis RelBE-like toxin-antitoxin complexes.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute and UCLA-DOE Institute for Genomics and Proteomics and Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095-1570, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Miallau
authors.forename: Paras
authors.initials: P
authors.lastname: Jain
authors.forename: Mark A
authors.initials: MA
authors.lastname: Arbing
authors.forename: Duilio
authors.initials: D
authors.lastname: Cascio
authors.forename: Tung
authors.initials: T
authors.lastname: Phan
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Ahn
authors.forename: Sum
authors.initials: S
authors.lastname: Chan
authors.forename: Irina
authors.initials: I
authors.lastname: Chernishof
authors.forename: Michelle
authors.initials: M
authors.lastname: Maxson
authors.forename: Janet
authors.initials: J
authors.lastname: Chiang
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.forename: David S
authors.initials: DS
authors.lastname: Eisenberg
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D000992:Antitoxins / Q000737:chemistry* / Q000235:genetics; D001427:Bacterial Toxins / Q000737:chemistry* / Q000235:genetics; D002384:Catalysis; D048430:Cell Shape / Q000235:genetics; D016000:Cluster Analysis; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000235:genetics; D020102:Mycobacterium smegmatis; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000235:genetics; D010802:Phylogeny; D011487:Protein Conformation; D040901:Proteomics / Q000379:methods; D016415:Sequence Alignment; D013045:Species Specificity
chemical_list: D000992:Antitoxins; D001427:Bacterial Toxins; D046912:Multiprotein Complexes