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J. Biol. Chem., Vol. 283, Issue 7, 4261-4271, February 15, 2008

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Staphylococcus aureus DsbA Does Not Have a Destabilizing Disulfide

A NEW PARADIGM FOR BACTERIAL OXIDATIVE FOLDING^*

Begoña Heras¹, Mareike Kurz, Russell Jarrott, Stephen R. Shouldice, Patrick Frei, Gautier Robin, Maa emaar, Linda Thöny-Meyer^¶, Rudi Glockshuber, and Jennifer L. Martin²

From the Institute for Molecular Bioscience, University of Queensland, Brisbane QLD 4072, Australia, the Institute of Molecular Biology and Biophysics, ETH Zürich CH-8093 Zürich, Switzerland, and the ^¶Laboratory for Biomaterials, EMPA, Lerchenfeldstrasse 5, CH-9014 St. Gallen, Switzerland

In Gram-negative bacteria, the introduction of disulfide bonds into folding proteins occurs in the periplasm and is catalyzed by donation of an energetically unstable disulfide from DsbA, which is subsequently re-oxidized through interaction with DsbB. Gram-positive bacteria lack a classic periplasm but nonetheless encode Dsb-like proteins. Staphylococcus aureus encodes just one Dsb protein, a DsbA, and no DsbB. Here we report the crystal structure of S. aureus DsbA (SaDsbA), which incorporates a thioredoxin fold with an inserted helical domain, like its Escherichia coli counterpart EcDsbA, but it lacks the characteristic hydrophobic patch and has a truncated binding groove near the active site. These findings suggest that SaDsbA has a different substrate specificity than EcDsbA. Thermodynamic studies indicate that the oxidized and reduced forms of SaDsbA are energetically equivalent, in contrast to the energetically unstable disulfide form of EcDsbA. Further, the partial complementation of EcDsbA by SaDsbA is independent of EcDsbB and biochemical assays show that SaDsbA does not interact with EcDsbB. The identical stabilities of oxidized and reduced SaDsbA may facilitate direct re-oxidation of the protein by extracellular oxidants, without the need for DsbB.

Received for publication, September 19, 2007 , and in revised form, November 14, 2007.

The atomic coordinates and structure factors (code 3BCI, 3BD2, and 3BCK) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by an Australian National Health and Medical Research Council (NHMRC) Senior Research Fellowship (to J. L. M.), Australian Research Council grants (to J. L. M. and to B. H.), a University of Queensland Early Career Researcher Grant (to B. H.), an International Post-graduate Research Scholarship (IPRS) (to M. K.), a University of Queensland Postdoctoral Fellowship (to S. R. S.), an ARC Postdoctoral fellowship (to M. C.), and the Schweizerische Nationalfonds within the framework of the NCCR Structural Biology Program (to R. G. and P. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence may be addressed: Queensland Bioscience Precinct, Bldg. 80 Carmody Rd, University of Queensland QLD 4072, Australia. Tel.: 61-7-33462020; Fax: 61-7-33462101; E-mail: bheras{at}imb.uq.edu.au.

² To whom correspondence may be addressed: Queensland Bioscience Precinct, Bldg 80 Carmody Rd, University of Queensland, QLD 4072, Australia. Tel.: 61-7-33462016; Fax: 61-7-33462101; E-mail: j.martin{at}imb.uq.edu.au.

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