Thioredoxinfold

Thioredoxinfold is a proposed protein structural fold class named for its resemblance to the thioredoxin fold while exhibiting distinctive topology. It describes proteins that adopt a thioredoxin-like scaffold but differ in the arrangement of beta strands and insertions in the loops surrounding the active site.

Structural features typically include a core beta-sheet composed of four to five beta strands, flanked by one or two alpha helices. A hallmark of thioredoxinfold proteins is the redox-active CXXC motif (commonly CGPC) located in a solvent-exposed loop joining the first beta strand to the adjacent helix, positioning the cysteine residues for disulfide exchange. Variants may display alterations in the loop length, additional helices, or insertions that modulate substrate access.

Many thioredoxinfold proteins act as oxidoreductases, catalyzing disulfide formation or rearrangement during protein folding and redox homeostasis. Some members have evolved regulatory or chaperone-like roles, relying on redox-sensing cysteines to respond to cellular conditions. Substrate specificity is largely determined by surface loops near the active site.

Distribution and relevance: The thioredoxinfold concept is used to classify related structures found across bacteria, archaea, and eukaryotes. It aids comparative analyses of redox-active proteins and informs protein engineering efforts aiming to alter redox properties or substrate scope.