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J. Biol. Chem., Vol. 281, Issue 8, 4911-4919, February 24, 2006

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Conserved Role of the Linker -Helix of the Bacterial Disulfide Isomerase DsbC in the Avoidance of Misoxidation by DsbB^*

Laura Segatori, Lori Murphy, Silvia Arredondo, Hiroshi Kadokura, Hiram Gilbert^¶, Jon Beckwith¹, and George Georgiou^||**2

From the Departments of Chemical Engineering and ^||Biomedical Engineering and ^**Institute for Cell and Molecular Biology, University of Texas, Austin, Texas 78712-1095, the Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115, and the Department of ^¶Biochemistry, Baylor College of Medicine, Houston, Texas 77030

In the bacterial periplasm the co-existence of a catalyst of disulfide bond formation (DsbA) that is maintained in an oxidized state and of a reduced enzyme that catalyzes the rearrangement of mispaired cysteine residues (DsbC) is important for the folding of proteins containing multiple disulfide bonds. The kinetic partitioning of the DsbA/DsbB and DsbC/DsbD pathways partly depends on the ability of DsbB to oxidize DsbA at rates >1000 times greater than DsbC. We show that the resistance of DsbC to oxidation by DsbB is abolished by deletions of one or more amino acids within the -helix that connects the N-terminal dimerization domain with the C-terminal thioredoxin domain. As a result, mutant DsbC carrying -helix deletions could catalyze disulfide bond formation and complemented the phenotypes of dsbA cells. Examination of DsbC homologues from Haemophilus influenzae, Pseudomonas aeruginosa, Erwinia chrysanthemi, Yersinia pseudotuberculosis, Vibrio cholerae (30-70% sequence identity with the Escherichia coli enzyme) revealed that the mechanism responsible for avoiding oxidation by DsbB is a general property of DsbC family enzymes. In addition we found that deletions in the linker region reduced, but did not abolish, the ability of DsbC to assist the formation of active vtPA and phytase in vivo, in a DsbD-dependent manner, revealing that interactions between DsbD and DsbC are also conserved.

Received for publication, May 18, 2005 , and in revised form, October 27, 2005.

^* This work was supported by National Institutes of Health Grants GM55090 and GM41883 (to J. B.). 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 Figs. S1-S7.

¹ An American Cancer Society Professor.

² To whom correspondence should be addressed. E-mail: gg{at}che.uteas.edu.

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