Thioredoxins [1, 2, 3, 4] are small disulphide-containing redox proteins that have been found in all the kingdoms of living organisms. Thioredoxin serves as a general protein disulphide oxidoreductase. It interacts with a broad range of proteins by a redox mechanism based on reversible oxidation of two cysteine thiol groups to a disulphide, accompanied by the transfer of two electrons and two protons. The net result is the covalent interconversion of a disulphide and a dithiol. In the NADPH-dependent protein disulphide reduction, thioredoxin reductase (TR) catalyses the reduction of oxidised thioredoxin (trx) by NADPH using FAD and its redox-active disulphide; reduced thioredoxin then directly reduces the disulphide in the substrate protein [5].
Thioredoxin is present in prokaryotes and eukaryotes and the sequence around the redox-active disulphide bond is well conserved. All thioredoxins contain a cis-proline located in a loop preceding beta-strand 4, which makes contact with the active site cysteines, and is important for stability and function [5]. Thioredoxin belongs to a structural family that includes glutaredoxin, glutathione peroxidase, bacterial protein disulphide isomerase DsbA, and the N-terminal domain of glutathione transferase [6]. Thioredoxins have a beta-alpha unit preceding the motif common to all these proteins.
A number of eukaryotic proteins contain domains evolutionary related to thioredoxin, most of them are protein disulphide isomerases (PDI). PDI (5.3.4.1) [6, 7, 8] is an endoplasmic reticulum multi-functional enzyme that catalyses the formation and rearrangement of disulphide bonds during protein folding [9]. All PDI contains two or three (ERp72) copies of the thioredoxin domain, each of which contributes to disulphide isomerase activity, but which are functionally non-equivalent [10]. Moreover, PDI exhibits chaperone-like activity towards proteins that contain no disulphide bonds, i.e. behaving independently of its disulphide isomerase activity [11]. The various forms of PDI which are currently known are:
- PDI major isozyme; a multifunctional protein that also function as the beta subunit of prolyl 4-hydroxylase (1.14.11.2), as a component of oligosaccharyl transferase (2.4.1.119), as thyroxine deiodinase (3.8.1.4), as glutathione-insulin transhydrogenase (1.8.4.2) and as a thyroid hormone-binding protein
- ERp60 (ER-60; 58 Kd microsomal protein). ERp60 was originally thought to be a phosphoinositide-specific phospholipase C isozyme and later to be a protease.
- ERp72.
- ERp5.
Bacterial proteins that act as thiol:disulphide interchange proteins that allows disulphide bond formation in some periplasmic proteins also contain a thioredoxin domain. These proteins include:
This entry represents the thioredoxin protein family.
1. Thioredoxin. Annu. Rev. Biochem. 54, 237-71
2. Thioredoxin and glutaredoxin systems. J. Biol. Chem. 264, 13963-6
3. Thioredoxin structure and mechanism: conformational changes on oxidation of the active-site sulfhydryls to a disulfide. Structure 3, 239-43
4. Thioredoxin--a fold for all reasons. Structure 3, 245-50
5. Crystal structure of thioredoxin-2 from Anabaena. Structure 3, 1097-108
6. Protein disulphide-isomerase: a homologue of thioredoxin implicated in the biosynthesis of secretory proteins. Biochem. Soc. Trans. 16, 96-9
7. Protein hydroxylation: prolyl 4-hydroxylase, an enzyme with four cosubstrates and a multifunctional subunit. FASEB J. 3, 1609-17
8. Protein disulphide isomerase: building bridges in protein folding. Trends Biochem. Sci. 19, 331-6
9. The role of the thiol/disulfide centers and peptide binding site in the chaperone and anti-chaperone activities of protein disulfide isomerase. J. Biol. Chem. 269, 19128-35
10. Mutations in the thioredoxin sites of protein disulfide isomerase reveal functional nonequivalence of the N- and C-terminal domains. J. Biol. Chem. 269, 30946-52
11. Chaperone-like activity of protein disulfide-isomerase in the refolding of rhodanese. Eur. J. Biochem. 231, 312-6
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