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J. Biol. Chem., Vol. 281, Issue 43, 32668-32675, October 27, 2006

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The Thioredoxin Domain of Neisseria gonorrhoeae PilB Can Use Electrons from DsbD to Reduce Downstream Methionine Sulfoxide Reductases^*

Nathan Brot, Jean-François Collet^¶1, Lynnette C. Johnson^||, Thomas J. Jönsson^||, Herbert Weissbach^**, and W. Todd Lowther^||2

From the Hospital for Special Surgery, Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021, the ^¶Christian de Duve Institute of Cellular Pathology, Universite Catholique de Louvain, BCHM-GRM Unit, 75-39 Avenue Hippocrate, 1200 Brussels, Belgium, the ^**Center for Molecular Biology and Biotechnology, Florida Atlantic University, Boca Raton, Florida 33431, and the ^||Center for Structural Biology, Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

The PilB protein from Neisseria gonorrhoeae is located in the periplasm and made up of three domains. The N-terminal, thioredoxin-like domain (NT domain) is fused to tandem methionine sulfoxide reductase A and B domains (MsrA/B). We show that the domain of Escherichia coli DsbD is able to reduce the oxidized NT domain, which suggests that DsbD in Neisseria can transfer electrons from the cytoplasmic thioredoxin to the periplasm for the reduction of the MsrA/B domains. An analysis of the available complete genomes provides further evidence for this proposition in other bacteria where DsbD/CcdA, Trx, MsrA, and MsrB gene homologs are all located in a gene cluster with a common transcriptional direction. An examination of wild-type PilB and a panel of Cys to Ser mutants of the full-length protein and the individually expressed domains have also shown that the NT domain more efficiently reduces the MsrA/B domains when in the polyprotein context. Within this frame-work there does not appear to be a preference for the NT domain to reduce the proximal MsrA domain over MsrB domain. Finally, we report the 1.6Å crystal structure of the NT domain. This structure confirms the presence of a surface loop that makes it different from other membrane-tethered, Trx-like molecules, including TlpA, CcmG, and ResA. Subtle differences are observed in this loop when compared with the Neisseria meningitidis NT domain structure. The data taken together supports the formation of specific NT domain interactions with the MsrA/B domains and its in vivo recycling partner, DsbD.

Received for publication, May 24, 2006 , and in revised form, July 11, 2006.

The atomic coordinates and structure factors (code 2H30) 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 developmental funds from the Wake Forest University School of Medicine. Use of the National Synchrotron Light Source, Brookhaven National Laboratory, was supported by the U.S. Dept. of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-98CH10886. 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 Chercheur Qualifié of the Belgian FNRS.

² To whom correspondence should be addressed: Center for Structural Biology, Dept. of Biochemistry, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. Tel.: 336-716-7230; Fax: 336-777-3242; E-mail: tlowther{at}wfubmc.edu.

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