Year: 2026
Type: article
Abstract: Thioredoxin-fold oxidoreductases drive oxidative protein folding and redox homeostasis across all domains of life. They catalyse thiol-disulfide exchange in diverse substrates, yet how they reconcile catalytic precision with substrate diversity remains unclear. Here we show, using high-resolution structures and functional analyses of the Escherichia coli oxidoreductase DsbA, that a conserved cis-proline loop adjacent to the catalytic Cys-Pro-His-Cys motif serves as a universal catalytic lock. The loop positions the substrate cysteine in a right-handed disulfide geometry optimal for exchange, while surrounding surfaces accommodate sequence variation. Substitution of the cis-proline abolishes turnover, whereas mutation of the preceding glycine preserves geometry but reduces efficiency. Comparative structural analyses demonstrate that this cis-proline-dependent hydrogen-bonding scaffold is conserved across thioredoxins, protein disulfide isomerases, peroxiredoxins and bacterial Dsb proteins. This conserved mechanism explains how catalytic fidelity is maintained while enabling substrate versatility and provides a foundation for enzyme engineering and therapeutic development.
Source: Communications Biology
Institutions: La Trobe University, Queensland University of Technology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,190
Awards: Dissecting the pathogenic triad of enteric pathogens: Assembly, structure and function of autotransporter proteases, Molecular control of a bacterial fight or flight response, How bacteria form resistant aggregates and biofilms, DsbA foldases from multidrug resistant pathogens as targets for new antimicrobials, Molecular mechanisms of novel bacterial copper defense proteins
OpenAlex ID: W7154273145