Rv2969c, essential for optimal growth in Mycobacterium tuberculosis, is a DsbA-like enzyme that interacts with VKOR-derived peptides and has atypical features of DsbA-like disulfide oxidases

Premkumar, Lakshmanane, Heras, Begoña, Duprez, Wilko, Walden, Patricia, Halili, Maria, Kurth, Fabian, Fairlie, David P. and Martin, Jennifer L. (2013) Rv2969c, essential for optimal growth in Mycobacterium tuberculosis, is a DsbA-like enzyme that interacts with VKOR-derived peptides and has atypical features of DsbA-like disulfide oxidases. Acta Crystallographica Section D: Biological Crystallography, 69 10: 1981-1994. doi:10.1107/S0907444913017800

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Author Premkumar, Lakshmanane
Heras, Begoña
Duprez, Wilko
Walden, Patricia
Halili, Maria
Kurth, Fabian
Fairlie, David P.
Martin, Jennifer L.
Title Rv2969c, essential for optimal growth in Mycobacterium tuberculosis, is a DsbA-like enzyme that interacts with VKOR-derived peptides and has atypical features of DsbA-like disulfide oxidases
Formatted title
Rv2969c, essential for optimal growth in Mycobacterium tuberculosis, is a DsbA-like enzyme that interacts with VKOR-derived peptides and has atypical features of DsbA-like disulfide oxidases
Journal name Acta Crystallographica Section D: Biological Crystallography   Check publisher's open access policy
ISSN 0907-4449
1399-0047
Publication date 2013-10
Sub-type Article (original research)
DOI 10.1107/S0907444913017800
Open Access Status File (Publisher version)
Volume 69
Issue 10
Start page 1981
End page 1994
Total pages 14
Place of publication Malden, MA, United States
Publisher Wiley-Blackwell Publishing
Collection year 2014
Language eng
Formatted abstract
The bacterial disulfide machinery is an attractive molecular target for developing new antibacterials because it is required for the production of multiple virulence factors. The archetypal disulfide oxidase proteins in Escherichia coli (Ec) are DsbA and DsbB, which together form a functional unit: DsbA introduces disulfides into folding proteins and DsbB reoxidizes DsbA to maintain it in the active form. In Mycobacterium tuberculosis (Mtb), no DsbB homologue is encoded but a functionally similar but structurally divergent protein, MtbVKOR, has been identified. Here, the Mtb protein Rv2969c is investigated and it is shown that it is the DsbA-like partner protein of MtbVKOR. It is found that it has the characteristic redox features of a DsbA-like protein: a highly acidic catalytic cysteine, a highly oxidizing potential and a destabilizing active-site disulfide bond. Rv2969c also has peptide-oxidizing activity and recognizes peptide segments derived from the periplasmic loops of MtbVKOR. Unlike the archetypal EcDsbA enzyme, Rv2969c has little or no activity in disulfide-reducing and disulfide-isomerase assays. The crystal structure of Rv2969c reveals a canonical DsbA fold comprising a thioredoxin domain with an embedded helical domain. However, Rv2969c diverges considerably from other DsbAs, including having an additional C-terminal helix (H8) that may restrain the mobility of the catalytic helix H1. The enzyme is also characterized by a very shallow hydrophobic binding surface and a negative electrostatic surface potential surrounding the catalytic cysteine. The structure of Rv2969c was also used to model the structure of a paralogous DsbA-like domain of the Ser/Thr protein kinase PknE. Together, these results show that Rv2969c is a DsbA-like protein with unique properties and a limited substrate-binding specificity.
Keyword DsbA
VKOR
DsbB
Antibacterial target
Oxidative folding
Virulence
Thioredoxin
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
 
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Created: Fri, 11 Oct 2013, 10:50:55 EST by Mrs Louise Nimwegen on behalf of Institute for Molecular Bioscience