Unveiling the thioredoxin fold: a systematic review and bioinformatic analysis of protein disulfide isomerase and Dsb family proteins

Introduction: Protein Disulfide Isomerases (PDIs) and bacterial Dsb proteins are key members of the thioredoxin-fold superfamily, essential for oxidative protein folding in eukaryotic and prokaryotic systems, respectively. Despite their differences in cellular context, these proteins share a conserved thioredoxin domain architecture that enables catalysis of disulfide bond formation, isomerization, and reduction. This systematic review integrates biochemical, structural, and bioinformatic data to identify conserved features within the PDI and Dsb families that underline their catalytic functions. Methods: Using a PRISMA-based methodology, we screened and analyzed 96 relevant articles and conducted a comparative structural analysis of 11 representative PDI proteins, most of which lack experimentally resolved structures. We leveraged AlphaFold models alongside crystal structures of canonical PDI (PDIA1), DsbC, and DsbG. Results: We reveal conserved tertiary folds, catalytic motifs, and domain arrangements across species. These findings highlight the evolutionary conservation and structural versatility of thioredoxin-fold enzymes and underscore their biomedical relevance in diseases linked to protein misfolding, such as neurodegeneration, cancer, and infection. Discussion: The results offer a foundation for future experimental studies and therapeutic exploration targeting redox-regulating thioredoxin-fold proteins.