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DSB proteins and bacterial pathogenicity

Nature Reviews Microbiology volume 7, pages 215–225 (2009)Cite this article

Key Points

  • A key rate-limiting step in protein folding is the introduction of correct disulphide bonds between cysteine residues in a process called oxidative protein folding. Organisms ranging from bacteria to humans use specialized machinery to perform this step, which is essential for the assembly and function of many secreted and membrane proteins.

  • The DSB (disulphide bond) protein family that performs oxidative folding in Escherichia coli K-12 has been comprehensively characterized, and this machinery has since become the paradigm for oxidative folding in all bacteria and archaea.

  • The E. coli K-12 complement of DSB proteins is not shared by all bacteria. Indeed, seven different disulphide bond-forming models have recently been proposed, and bacterial genomic analysis suggests that many more are likely to be encoded. Clearly, our current concept of the bacterial DSB machinery and how it operates will need to change.

  • Importantly, many pathogenic bacteria have developed distinct DSB systems. In these organisms, DSB proteins have a pivotal role in the generation of virulence factors and can contribute to pathogenicity. The increasing volume of evidence linking DSB proteins to virulence identifies these proteins as targets for novel antibacterial drugs.

  • Bacterial infection remains a major cause of death and disease worldwide, and antibiotic resistance is on the rise. Consequently, there is a pressing need for new, validated antibacterial drug targets. The possibility of targeting DSB proteins to attenuate bacterial virulence represents an innovative approach to combat bacterial infection and antibiotic resistance.

Abstract

If DNA is the information of life, then proteins are the machines of life — but they must be assembled and correctly folded to function. A key step in the protein-folding pathway is the introduction of disulphide bonds between cysteine residues in a process called oxidative protein folding. Many bacteria use an oxidative protein-folding machinery to assemble proteins that are essential for cell integrity and to produce virulence factors. Although our current knowledge of this machinery stems largely from Escherichia coli K-12, this view must now be adjusted to encompass the wider range of disulphide catalytic systems present in bacteria.

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Figure 1: Disulphide bonds.
Figure 2: The DSB machinery in the periplasm of Escherichia coli K-12.
Figure 3: Schematic of the different types of oxidative pathways found so far in bacteria.
Figure 4: Representative phylogenetic tree that shows the distribution of DsbAs in bacteria and archaea.
Figure 5: Overview of selected virulence mechanisms that are dependent on DsbA-mediated disulphide bond formation.

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Acknowledgements

This work was supported by the Australian Research Council (grants to B.H. M.J.S. M.A.S. and J.L.M.), the Australian National Health and Medical Research Council (grants to J.L.M., M.J.S. and B.H., M.A.S. and a fellowship to J.L.M.) and the University of Queensland (postdoctoral fellowship to S.R.S.). We also acknowledge the support of the Australian Research Council Special Research Centre for Functional and Applied Genomics.

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Authors and Affiliations

  1. The University of Queensland, Institute for Molecular Bioscience, Queensland, 4072, Australia

    Begoña Heras, Stephen R. Shouldice & Jennifer L. Martin

  2. The University of Queensland, School of Molecular and Microbial Sciences, Queensland, 4072, Australia

    Makrina Totsika & Mark A. Schembri

  3. Monash University, Faculty of Pharmacy and Pharmaceutical Sciences, Victoria, 3052, Australia

    Martin J. Scanlon

Authors
  1. Begoña Heras
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  2. Stephen R. Shouldice
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  3. Makrina Totsika
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  4. Martin J. Scanlon
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  5. Mark A. Schembri
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  6. Jennifer L. Martin
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Correspondence to Begoña Heras or Jennifer L. Martin.

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DATABASES

Entrez Genome Project

Bacillus cereus

Bacillus subtilis

Bordetella pertussis

Deinococcus radiodurans

Escherichia coli K-12

Klebsiella oxytoca

Listeria innocua

Listeria monocytogenes

Mycobacterium tuberculosis

Neisseria meningitidis

Proteus mirabilis

Pseudomonas aeruginosa

Salmonella enterica subsp. enterica serovar Typhimurium

Shewanella oneidensis

Shigella flexneri

Staphylococcus aureus

Streptococcus pyogenes

Vibrio cholerae

Wolbachia pipientis

Yersinia pestis

FURTHER INFORMATION

Jennifer L. Martin's homepage

iTOL

J. Craig Venter Institute

Glossary

Disulphide bond

A covalent S–S bond formed between two thiols; in this Review, the term disulphide bond refers to the bond between two cysteine residues.

Cysteine

An amino acid with a thiol side chain.

Fimbriae

Thin, thread-like organelles that are composed of multiple protein subunits, extend from the surface of the bacterial cell and mediate adhesion.

DsbA

A highly oxidizing protein in bacteria that catalyses disulphide bond formation in substrate proteins.

DsbB

The partner protein of DsbA that keeps DsbA in the active oxidized form.

Thiol

A chemical group that comprises a sulphur molecule bonded to a hydrogen molecule.

DsbC

A disulphide isomerase that proofreads and shuffles incorrectly formed disulphides.

Disulphide isomerization

The shuffling of non-native protein disulphide bonds to form native disulphide bonds.

DsbG

A protein that is thought to be a disulphide isomerase, similarly to DsbC, but for which no in vivo substrates have yet been identified.

DsbD

The partner protein of DsbC that keeps DsbC in the active reduced form.

DsbL

A protein that has a similar function to DsbA, but has a narrower substrate specificity.

DsbI

A protein that has a similar function to DsbB and is the partner protein for DsbL.

Chaperone–usher pathway

Mechanism by which multi-subunit fimbriae are produced in many Gram-negative bacteria.

Oxidative protein folding

The catalysed process by which disulphide bonds are incorporated into secreted and membrane proteins during folding to impart stability and activity.

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Heras, B., Shouldice, S., Totsika, M. et al. DSB proteins and bacterial pathogenicity. Nat Rev Microbiol 7, 215–225 (2009). https://doi.org/10.1038/nrmicro2087

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