Structure of the Acinetobacter baumannii dithiol oxidase DsbA bound to EF-Tu reveals a novel protein interaction site

Premkumar, Lakshmanane, Kurth, Fabian, Duprez, Wilko, Grøftehauge, Morten K., King, Gordon J., Halili, Maria A., Heras, Begoña and Martin, Jennifer L. (2014) Structure of the Acinetobacter baumannii dithiol oxidase DsbA bound to EF-Tu reveals a novel protein interaction site. Journal of Biological Chemistry, 289 29: 19869-19880. doi:10.1074/jbc.M114.571737

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Author Premkumar, Lakshmanane
Kurth, Fabian
Duprez, Wilko
Grøftehauge, Morten K.
King, Gordon J.
Halili, Maria A.
Heras, Begoña
Martin, Jennifer L.
Title Structure of the Acinetobacter baumannii dithiol oxidase DsbA bound to EF-Tu reveals a novel protein interaction site
Formatted title
Structure of the Acinetobacter baumannii dithiol oxidase DsbA bound to EF-Tu reveals a novel protein interaction site
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
1083-351X
Publication date 2014-05-23
Year available 2014
Sub-type Article (original research)
DOI 10.1074/jbc.M114.571737
Open Access Status File (Publisher version)
Volume 289
Issue 29
Start page 19869
End page 19880
Total pages 12
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Formatted abstract
Background: DsbA is a master virulence determinant of bacterial pathogens and a target for antivirulence drugs.
Results: AbDsbA is a class I dithiol oxidase that binds EF-Tu-derived and DsbB-derived peptides on different enzyme surfaces.
Conclusion: Discovery of high affinity peptide interaction sites provides a platform for inhibitor design.
Significance: AbDsbA inhibitors could have anti-biofilm activity against multidrug resistant Acinetobacter baumannii.

The multidrug resistant bacterium Acinetobacter baumannii is a significant cause of nosocomial infection. Biofilm formation - that requires both disulfide bond forming and chaperone-usher pathways - is a major virulence trait in this bacterium. Our biochemical characterizations show that the periplasmic A. baumannii DsbA (AbDsbA) enzyme has an oxidizing redox potential and dithiol oxidase activity. We found an unexpected non-covalent interaction between AbDsbA and the highly conserved prokaryotic elongation factor, EF-Tu. EF-Tu is a cytoplasmic protein but has been localized extracellularly in many bacterial pathogens. The crystal structure of this complex revealed that the EF-Tu switch I region binds to the non-catalytic surface of AbDsbA. Though the physiological and pathological significance of a DsbA/EF-Tu association is unknown, peptides derived from the EF-Tu switch I region bound to AbDsbA with submicromolar affinity. We also identified a 7-residue DsbB-derived peptide that bound to AbDsbA with low micromolar affinity. Further characterization confirmed that the EF-Tu and DsbB derived peptides bind at two distinct sites. These data point to the possibility that the non-catalytic surface of DsbA is a potential substrate or regulatory protein interaction site. The two peptides identified in this work, together with the newly characterized interaction site, provide a novel starting point for inhibitor design targeting AbDsbA.
Keyword Multidrug resistance
Disulfide bond formation
DsbA
Anti-biofilm formation
Antivirulence
Bacterial infection
Crystallography
Enzyme catalysis
Peptides
Protein structure
Protein-protein interaction
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes First Published on May 23, 2014.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Thu, 29 May 2014, 04:23:59 EST by Prem Lakshmanane on behalf of Institute for Molecular Bioscience