InterPro: IPR017937 Thioredoxin, conserved site

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 [1].

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 [4]. 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 (EC: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 (EC:1.14.11.2), as a component of oligosaccharyl transferase (EC:2.4.1.119), as thyroxine deiodinase (EC:3.8.1.4), as glutathione-insulin transhydrogenase (EC: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 are:

• Escherichia coli DsbA (or PrfA) and its orthologs in Vibrio cholerae (TtcpG) and Haemophilus influenzae (Por).
• E. coli DsbC (or XpRA) and its orthologues in Erwinia chrysanthemi and H. influenzae.
• E. coli DsbD (or DipZ) and its H. influenzae orthologue.
• E. coli DsbE (or CcmG) and orthologues in H. influenzae.
• Rhodobacter capsulatus (Rhodopseudomonas capsulata) (HelX), Rhiziobiacae (CycY and TlpA).

This entry represents a conserved site found in the thioredoxin domain. This site contains two cysteines that form the redox-active disulphide bond.