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Disulfide bond formation in the bacterial periplasm: major achievements and challenges ahead.

ABSTRACT: The discovery of the oxidoreductase disulfide bond protein A (DsbA) in 1991 opened the way to the unraveling of the pathways of disulfide bond formation in the periplasm of Escherichia coli and other Gram-negative bacteria. Correct oxidative protein folding in the E. coli envelope depends on both the DsbA/DsbB pathway, which catalyzes disulfide bond formation, and the DsbC/DsbD pathway, which catalyzes disulfide bond isomerization.Recent data have revealed an unsuspected link between the oxidative protein-folding pathways and the defense mechanisms against oxidative stress. Moreover, bacterial disulfide-bond-forming systems that differ from those at play in E. coli have been discovered.In this review, we discuss fundamental questions that remain unsolved, such as what is the mechanism employed by DsbD to catalyze the transfer of reducing equivalents across the membrane and how do the oxidative protein-folding catalysts DsbA and DsbC cooperate with the periplasmic chaperones in the folding of secreted proteins.Understanding the mechanism of DsbD will require solving the structure of the membranous domain of this protein. Another challenge of the coming years will be to put the knowledge of the disulfide formation machineries into the global cellular context to unravel the interplay between protein-folding catalysts and chaperones. Also, a thorough characterization of the disulfide bond formation machineries at work in pathogenic bacteria is necessary to design antimicrobial drugs targeting the folding pathway of virulence factors stabilized by disulfide bonds.

SUBMITTER: Denoncin K

PROVIDER: S-EPMC3676657 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Disulfide bond formation in the bacterial periplasm: major achievements and challenges ahead.

Denoncin Katleen K Collet Jean-François JF

Antioxidants & redox signaling 20121002 1

<h4>Significance</h4>The discovery of the oxidoreductase disulfide bond protein A (DsbA) in 1991 opened the way to the unraveling of the pathways of disulfide bond formation in the periplasm of Escherichia coli and other Gram-negative bacteria. Correct oxidative protein folding in the E. coli envelope depends on both the DsbA/DsbB pathway, which catalyzes disulfide bond formation, and the DsbC/DsbD pathway, which catalyzes disulfide bond isomerization.<h4>Recent advances</h4>Recent data have rev ...[more]

PMID: 22901060

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Project description:The protein secretory pathway must maintain homoeostasis while producing a wide assortment of proteins in different conditions. It is also used extensively to produce many useful proteins in biotechnology. As such, secretory pathway dysfunction can be highly detrimental to the cell, resulting in the molecular basis for many human diseases, and can drastically inhibit product titers in biochemical production. Because the secretory pathway is a highly-integrated, multi-organelle system, dysfunction can happen at many levels and dissecting the root cause can be challenging. To better understand some of these dysfunctions, we measured multiple systems-level states of the cell (physiology, transcriptome, metabolism) while secreting a small protein (insulin precursor) or a large protein (?-amylase). This was carried out in the presence and absence of HAC1, a key transcription factor in maintaining secretory homeostasis. Clear trends in cellular stress were apparent across multiple data resulting from our perturbations. In particular, processes involving (1) degradation of protein / recycling amino acids, (2) overall transcription/translation repression, and (3) oxidative stress. Apparent runaway oxidative radical production was explained by a thermodynamic model that we put forward for disulfide formation in the endoplasmic reticulum. This model predicts that balancing the relative rates of protein folding and disulfide bond formation are key to easing oxidative stress. These predictions have direct implications in how to engineer a broad range of recombinant proteins for secretion and provide potential hypotheses for the root causes of several secretory-associated diseases. Yeast strains were constructed that produce and secrete (a) IP or (b) ?-amylase and were compared to yeast strains containing (c) an empty vector in both wild-type and HAC1 deletion backgrounds. These strains are named WN (WT with empty vector), WI (WT secreting IP), WA (WT secreting ?-amylase), dN (?hac1 with empty vector), dI (?hac1 secreting IP), and dA (?hac1 secreting ?-amylase). Strains were characterized in batch fermentation and samples were taken in mid-exponential phase. Triplicate fermentations were carried out for each strain.

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Disulfide bond formation in the bacterial periplasm: major achievements and challenges ahead.

Publications

Disulfide bond formation in the bacterial periplasm: major achievements and challenges ahead.

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