Thioredoxins are small disulfide-containing redox proteins that have been found in all the kingdoms of living organisms. Thioredoxin serves as a general protein disulfide oxidoreductase. It interacts with a broad range of proteins by a redox mechanism based on reversible oxidation of 2

cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...

thiol group In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...

s to a

disulfide In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...

, accompanied by the transfer of 2 electrons and 2 protons. The net result is the covalent interconversion of a disulfide and a dithiol. TR-S₂ + NADPH + H⁺ -> TR-(SH)₂ + NADP⁺ (1) trx-S₂ + TR-(SH)₂ -> trx-(SH)₂ + TR-S₂ (2) Protein-S₂ + trx-(SH)₂ -> Protein-(SH)₂ + trx-S₂ (3) In the NADPH-dependent protein disulfide reduction,

thioredoxin reductase Thioredoxin reductases (TR, TrxR) () are enzymes that reduce thioredoxin (Trx). Two classes of thioredoxin reductase have been identified: one class in bacteria and some eukaryotes and one in animals. In bacteria TrxR also catalyzes the reduction ...

(TR) catalyses reduction of oxidised thioredoxin (trx) by

NADPH Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NAD ...

using

FAD A fad or trend is any form of collective behavior that develops within a culture, a generation or social group in which a group of people enthusiastically follow an impulse for a short period. Fads are objects or behaviors that achieve short- ...

and its redox-active disulfide (steps 1 and 2). Reduced thioredoxin then directly reduces the disulfide in the substrate protein (step 3).

Protein disulfide isomerase Protein disulfide isomerase (), or PDI, is an enzyme in the endoplasmic reticulum (ER) in eukaryotes and the periplasm of bacteria that catalyzes the formation and breakage of disulfide bonds between cysteine residues within proteins as they ...

(PDI), a resident

foldase In molecular biology, foldases are a particular kind of molecular chaperones that assist the non-covalent folding of proteins in an ATP-dependent manner. Examples of foldase systems are the GroEL/GroES and the DnaK/DnaJ/GrpE system. References {{ ...

of the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

, is a multi-functional protein that catalyses the formation and isomerisation of disulfide bonds during protein folding. PDI contains 2 redox active domains, near the N- and

C-termini The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

, that are similar to thioredoxin: both contribute to disulfide isomerase activity, but are functionally non-equivalent. A mutant PDI, with all 4 of the active cysteines replaced by

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...

, displays a low but detectable level of disulfide isomerase activity. Moreover, PDI exhibits chaperone-like activity towards proteins that contain no disulfide bonds, i.e. behaving independently of its disulfide isomerase activity. A number of endoplasmic reticulum proteins that differ from the PDI major isozyme contain 2 ( ERp60, ERp5) or 3 (ERp72) thioredoxin domains; all of them seem to be PDIs. 3D-structures have been determined for a number of thioredoxins. The molecule has a doubly wound alternating alpha/beta fold, consisting of a 5-stranded parallel

beta-sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a g ...

core, enclosed by 4

alpha-helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...

. The active site disulfide is located at the N-terminus of helix 2 in a short segment that is separated from the rest of the helix by a kink caused by a conserved proline. The 4-membered disulfide ring is located on the surface of the protein. A flat hydrophobic surface lies adjacent to the disulfide, which presumably facilitates interaction with other proteins. One invariant feature of all thioredoxins is a

cis-proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...

located in a loop preceding beta-strand 4. This residue is positioned in van der Waals contact with the active site cysteines and is important both for stability and function. Thioredoxin belongs to a structural family that includes

glutaredoxin Glutaredoxins (also known as Thioltransferase) are small redox enzymes of approximately one hundred amino-acid residues that use glutathione as a cofactor. In humans this oxidation repair enzyme is also known to participate in many cellular functi ...

glutathione peroxidase Glutathione peroxidase (GPx) () is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage. The biochemical function of glutathione peroxidase is to reduce lipid h ...

, bacterial protein disulfide isomerase

DsbA DsbA is a bacterial List of bacterial disulfide oxidoreductases, thiol disulfide oxidoreductase (TDOR). DsbA is a key component of the Dsb (disulfide bond) family of enzymes. DsbA catalyzes intrachain disulfide bond formation as peptides emerg ...

, and the N-terminal domain of

glutathione transferase Glutathione ''S''-transferases (GSTs), previously known as ligandins, are a family of eukaryotic and prokaryotic phase II metabolic isozymes best known for their ability to catalyze the conjugation of the reduced form of glutathione (GSH) to x ...

. Thioredoxins have a beta-alpha unit preceding the motif common to all these proteins.

Human proteins containing thioredoxin domain

DNAJC10; ERP70;

GLRX3 Glutaredoxin-3 is a protein that in humans is encoded by the ''GLRX3'' gene. Interactions GLRX3 has been shown to interact with PRKCQ Protein kinase C theta (PKC-θ) is an enzyme that in humans is encoded by the ''PRKCQ'' gene. PKC-θ, a member ...

;

P4HB Protein disulfide-isomerase, also known as the beta- subunit of prolyl 4-hydroxylase (P4HB), is an enzyme that in humans encoded by the ''P4HB'' gene. The human ''P4HB'' gene is localized in chromosome 17q25. Unlike other prolyl 4-hydroxylase fami ...

;

PDIA2 Protein disulfide isomerase family A member 2 is a protein that in humans is encoded by the PDIA2 gene. Function This gene encodes a member of the Protein disulfide-isomerase, disulfide isomerase (PDI) family of endoplasmic reticulum (ER) pro ...

(PDIP);

PDIA3 Protein disulfide-isomerase A3 (PDIA3), also known as glucose-regulated protein, 58-kD (GRP58), is an isomerase enzyme. This protein localizes to the endoplasmic reticulum (ER) and interacts with lectin chaperones calreticulin and calnexin (CNX) ...

; PDIA4; PDIA5; PDIA6; PDILT;

QSOX1 Sulfhydryl oxidase 1 is an enzyme that in humans is encoded by the ''QSOX1'' gene. This gene encodes a protein that contains domains of thioredoxin and ERV1, members of two long-standing gene families. The gene expression is induced as fibroblast ...

; QSOX2; STRF8; TXN;

TXN2 Thioredoxin, mitochondrial also known as thioredoxin-2 is a protein that in humans is encoded by the ''TXN2'' gene on chromosome 22. This nuclear gene encodes a mitochondrial member of the thioredoxin family, a group of small multifunctional redox ...

; TXNDC1; TXNDC10; TXNDC11; TXNDC13; TXNDC14; TXNDC15; TXNDC16; TXNDC2; TXNDC3;

TXNDC4 Endoplasmic reticulum resident protein 44 (ERp44) also known as thioredoxin domain-containing protein 4 (TXNDC4) is a protein that in humans is encoded by the ''ERP44'' gene. Interactions TXNDC4 has been shown to interact with ERO1L ERO1-lik ...

; TXNDC5; TXNDC6; TXNDC8; TXNL1; TXNL3;

References

{{DEFAULTSORT:Thioredoxin Domain Protein domains Protein families