Disulfide oxidoreductases are viewed as foldases that help to maintain proteins on productive folding pathways by enhancing the rate of protein folding through the catalytic incorporation of disulfide bonds. SrgA, encoded on the virulence plasmid pStSR100 of Salmonella enterica serovar Typhimurium and located downstream of the plasmid-borne fimbrial operon, is a disulfide oxidoreductase. Sequence analysis indicates that SrgA is similar to DsbA from, for example, Escherichia coli, but not as highly conserved as most of the chromosomally encoded disulfide oxidoreductases from members of the family Enterobacteriaceae. SrgA is localized to the periplasm, and its disulfide oxidoreductase activity is dependent upon the presence of functional DsbB, the protein that is also responsible for reoxidation of the major disulfide oxidoreductase, DsbA. A quantitative analysis of the disulfide oxidoreductase activity of SrgA showed that SrgA was less efficient than DsbA at introducing disulfide bonds into the substrate alkaline phosphatase, suggesting that SrgA is more substrate specific than DsbA. It was also demonstrated that the disulfide oxidoreductase activity of SrgA is necessary for the production of plasmid-encoded fimbriae. The major structural subunit of the plasmidencoded fimbriae, PefA, contains a disulfide bond that must be oxidized in order for PefA stability to be maintained and for plasmid-encoded fimbriae to be assembled. SrgA efficiently oxidizes the disulfide bond of PefA, while the S. enterica serovar Typhimurium chromosomally encoded disulfide oxidoreductase DsbA does not. pefA and srgA were also specifically expressed at pH 5.1 but not at pH 7.0, suggesting that the regulatory mechanisms involved in pef gene expression are also involved in srgA expression. SrgA therefore appears to be a substrate-specific disulfide oxidoreductase, thus explaining the requirement for an additional catalyst of disulfide bond formation in addition to DsbA of S. enterica serovar Typhimurium.The ability of the bacterial cell to synthesize and secrete specific proteins is dependent upon several aspects of protein secretory pathways. While the passage of proteins through the secretory apparatus in the inner membrane has been relatively well studied (reviewed in references 18, 42, and 60), the events occurring once proteins reach the periplasm of gram-negative cells are less well understood. Even though the periplasm may not be their final destination, proteins begin the process of conformational folding once they reach the periplasm (74). This folding is accompanied by proline isomerization and disulfide bond formation, both necessary to attaining and maintaining native structure (23). These processes are mediated by peptidyl-prolyl isomerases (45) and disulfide oxidoreductases (2, 50, 56) that are present in the periplasm.Many proteinaceous structures, such as fimbriae (39, 78), flagella (14), and several bacterial toxins (46,53,65,77), either contain disulfide bonds or require disulfide bonds in some component of their assembly...
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