Protein Disulfide Exchange by the Intramembrane Enzymes DsbB, DsbD, and CcdA

• Published in: Journal of molecular biology 2020-08, Vol.432 (18), p.5091-5103
• Main Author: Bushweller, John H.
• Format: Article
• Language: English
• Subjects: Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; CcdA; Cell Membrane - enzymology; Disulfides - metabolism; DsbA; DsbB; DsbC; DsbD; Escherichia coli - metabolism; Escherichia coli Proteins - chemistry; Escherichia coli Proteins - metabolism; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Models, Molecular; Oxidoreductases - chemistry; Oxidoreductases - metabolism; Protein Conformation
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2020.04.008

The formation of disulfide bonds in proteins is an essential process in both prokaryotes and eukaryotes. In gram-negative bacteria including Escherichia coli, the proteins DsbA and DsbB mediate the formation of disulfide bonds in the periplasm. DsbA acts as the periplasmic oxidant of periplasmic substrate proteins. DsbA is reoxidized by transfer of reducing equivalents to the 4 TM helix membrane protein DsbB, which transfers reducing equivalents to ubiquinone or menaquinone. Multiple structural studies of DsbB have provided detailed structural information on intermediates in the process of DsbB catalyzed oxidation of DsbA. These structures and the insights gained are described. In proteins with more than one pair of Cys residues, there is the potential for formation of non-native disulfide bonds, making it necessary for the cell to have a mechanism for the isomerization of such non-native disulfide bonds. In E. coli, this is mediated by the proteins DsbC and DsbD. DsbC reduces mis-formed disulfide bonds. The eight-TM-helix protein DsbD reduces DsbC and is itself reduced by cytoplasmic thioredoxin. DsbD also contributes reducing equivalents for the reduction of cytochrome c to facilitate heme attachment. The DsbD functional homolog CcdA is a six-TM-helix membrane protein that provides reducing equivalents for the reduction of cytochrome c. A recent structure determination of CcdA has provided critical insights into how reducing equivalents are transferred across the membrane that likely also provides understanding how this is achieved by DsbD as well. This structure and the insights gained are described. [Display omitted] •Protein disulfide bond formation is catalyzed by DsbA and the membrane protein DsbB.•Multiple structural studies of DsbB provided key insights into DsbB function.•Protein disulfide reduction is essential for isomerization and cytochrome c activity.•Membrane protein DsbD provides reducing equivalents to periplasmic substrates.•Structure of DsbD homolog CcdA provides key insights into CcdA, DsbD function.