Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Thioredoxin (TXN)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101939


Historical Background

The name thioredoxin (Trx) was first introduced by Peter Reichard for the enzyme providing electrons needed for the enzymatic reaction of ribonucleotide reductase, in 1964 (Buchanan et al. 2012). However, Trxs have been described in yeast before, using different names: fraction C of the sulfate-reducing system and enzyme II of the enzymatic system reducing L-methionine sulfoxide. E. coli Trx1 was sequenced in 1968, revealing the characteristic Cys-Gly-Pro-Cys active site motif. In 1975, the crystal structure of oxidized E. coli Trx1 was solved, describing the characteristic Trx fold for the first time. The role of essential plant proteins for the process of photosynthesis, identified as Trxs in 1976–1978, is one of the first descriptions of biological redox regulation (Buchanan et al. 2012). All these mentioned early advances resulted in the first conference on thioredoxin at the University of California/Berkeley in 1981 and led to the further, extensive characterization of a protein which is now recognized as an important signaling molecule with more than 10,000 NCBI entries.

Thioredoxin Fold Proteins

The primary structure of the cytosolic Trx1 contains approximately 100 amino acids leading to a protein of approximately 12 kDa. The mitochondrial form is bigger due to a specific mitochondrial transit signal peptide at the N-terminus of the protein. Characteristic amino acids of Trxs include the Cys-Gly-Pro-Cys active site motif that is conserved throughout evolution and is essential for the oxidoreductase activity of the enzymes. The composition of the active site motif and surrounding amino acids determine the specific activity of the Trx fold proteins, e.g., via the redox potential. The calculated redox potential of the reductase Trx is −270 mV; the one of the related oxidase DsbA, for instance, is −122 mV. Moreover, Trxs contain a conserved cis-proline which is located opposite of the active site motif in the folded protein (Berndt and Lillig 2009).

Trxs have been described as highly structured proteins, due to the fact that 75–90% of the amino acid residues are involved in the formation of secondary structural elements. Trxs share a structural motif that comprises a core of three parallel and two antiparallel beta sheets, surrounded by four alpha helices (Fig. 1). Note that the exact number of β-sheets and α-helices can slightly differ between proteins of different organisms and species. The active site motif Cys-Gly-Pro-Cys is located at the loop between the first α-helix and the first β-sheet. It was shown by laboratory resurrections of Precambrian Trxs and 3D analysis that even though there are differences in the primary structure throughout evolution, the Trx fold has been remarkably conserved over the last 4 billion years (Ingles-Prieto et al. 2013). Numerous proteins with a variety of functions display the Trx fold and are classified as Trx family proteins. Next to other oxidoreductases such as glutaredoxins (Grx), peroxiredoxins (Prx), or protein disulfide isomerases, functionally different proteins like glutathione transferases, blue copper proteins, or chloride intracellular channels display this structural motif (Berndt and Lillig 2009).
Thioredoxin (TXN), Fig. 1

Thioredoxin fold. Crystal structure of reduced human Trx1 (PDB code 1ERT), active site cysteines (Cys32 and Cys35), and extra cysteines (Cys62, Cys69, and Cys73) are highlighted, and respective posttranslational modifications are mentioned

Analyzing the tertiary structure of different Trx molecules, Eklund and colleagues described the active site region as flat with a hydrophobic region for the interaction with substrates and a cluster of charged amino acids potentially being involved in the redox mechanisms during catalysis (Eklund et al. 1984). Recently, the electrostatic surface potentials of various members of the Trx family and their impact on protein interactions were elucidated as determinant for substrate specificity (Deponte and Lillig 2015) (Berndt et al. 2015). Both, cytosolic Trx1 and mitochondrial Trx2, have a comparably strong negative charge distribution pattern on the surface that is not affected by the redox state of the protein. The authors stated that the substrate specificity of the different members of the Trx family depends on (i) kinetic constraints, (ii) complementary molecular geometries, and (iii) electrostatic surfaces; the latter was for instance shown for specific interactions of human Trx1 with the NF-κB subunit p50 and Ref1, as well as E. coli Trx1 with 3′-phosphoadenosine-5′-Phosphosalfate (PAPS) reductase. Using PAPS reductase as model substrate, it was shown that the reduction of this protein does not depend on the redox potential of the respective oxidoreductase but on its electrostatic and geometric complementarity. In fact, efficiency of enzymatic reactivity correlates with the extent of the electric field created by the oxidoreductases. Another feature regulating interactions with other proteins is entropy (Palde and Carroll 2015). The authors described that the interaction between Trxs and oxidized substrates is favored which is based on small structural differences between oxidized and reduced substrates. Upon reduction, Trxs undergo small conformational changes mainly located in the active site. These changes affect the binding activity of reduced Trx to proteins, e.g., apoptosis signal-regulating kinase 1 (ASK-1), a mitogen-activated protein (MAP) kinase kinase kinase, required for induction of apoptosis. Whereas reduced Trx forms an apoptosis-inhibiting complex with ASK-1, oxidation of Trx leads to dissociation of this complex. Therefore, not only the redox state of the substrate but also the redox state of Trx controls intermolecular binding and thus specificity of enzymatic activity (Hanschmann et al. 2013).

Although the Cys-X-X-Cys motif has been described to be involved in metal binding in various proteins including binding of iron and cadmium (Berndt and Lillig 2009), E. coli Trx2 is so far the only example of a Trx binding metal ions in vivo. Trx2 uses two additional N-terminal Cys-X-X-Cys motifs to coordinate zinc (Collet et al. 2003). Interestingly, it is known that the conserved cis-proline prevents Trx from binding metal ligands via the active site motif, as well as the conserved Gly-Pro residues in between the two cysteine residues. The exchange of the cis-proline to histidine enables copper binding by the Trx fold protein Sco1. Grxs, closely related oxidoreductases, lacking a proline within the active site, were shown to coordinate Fe2S2 clusters with a unique assembly mode that involves the N-terminal active site cysteine residue of two monomers, as well as two molecules of glutathione that are non-covalently bound to the proteins. Several studies investigated metal binding using Trx as model (Berndt and Lillig 2009). In general, Trx became a model for protein folding, dynamics, function, and evolution (Vazquez et al. 2015).

Thioredoxins in all Kingdoms of Life

Trxs are highly conserved proteins found in all kingdoms of life: archaea, bacteria, and plants including cyanobacteria, fungi, and animals. To our knowledge, every organism contains at least one Trx protein. In higher organisms, Trxs are located in different compartments of the cell (Fig. 2). As mentioned above, the mammalian mitochondrial Trx2 has an N-terminal transit sequence. The cytosolic Trx1 was shown to translocate into the nucleus, for instance, upon UV irradiation or hypoxia, even though it lacks a specific nuclear localization signal. Hirota and colleagues demonstrated that the redox state of the protein does not seem to affect the translocation process, because all Cys/Ser mutants retained the ability of nuclear translocation (Hirota et al. 1999). Trx1 was also shown to be secreted as full-length protein and as a smaller version of the protein, named Trx80, only containing the first 80 amino acids (Hanschmann et al. 2013). The distinct mechanisms of Trx1 secretion to the extracellular space are, however, not well understood. Plants contain many more Trxs than mammals/vertebrates. The genome of A. thaliana, for instance, encodes at least 20 Trxs. Plant Trxs are divided into the subfamilies f, m, x, y, z (located in plastids), o (located in mitochondria), and h (located mainly in the cytosol) (Meyer et al. 2012) (Fig. 2).
Thioredoxin (TXN), Fig. 2

Thioredoxins in all kingdoms of life. In eukaryotes, Trxs are localized in different organelles. Trx1 is localized in the cytosol and the nucleus (not shown) and Trx2 in mitochondria. Plant plastids contain the most Trx subfamilies

Although Trxs are highly conserved, significant changes have occurred during evolution. For instance, the number of cysteinyl residues of Trx1 increased. E. coli Trx1, for instance, only contains the two active site cysteinyl residues, whereas mammalian Trx1 contains additional three cysteines, Cys62, Cys69, and Cys73. Cys62 and Cys69 are located within helix α3, and Cys73 is located on a hydrophobic region of the protein surface (Hashemy and Holmgren 2008). These additional cysteines have been shown to be involved in the dimerization and – via posttranslational modifications – in the regulation of the protein (see 3) (Fig. 1). Note that mitochondrial Trx2 does not contain these extra cysteines.

Thioredoxin System and Enzymatic Reactions

Oxidized Trx is reduced by the Trx system consisting of NADPH and the flavo-enzyme thioredoxin reductase (TrxR) that was first described by Peter Reichard in 1964 (Fig. 3). Two different types of TrxRs exist: a low molecular weight protein in archaea, bacteria, fungi, and plants and a high molecular weight selenoprotein in the remaining higher eukaryotes. In line with the Trx location, a cytosolic TrxR1 and a mitochondrial TrxR2 exist in mammals. In addition, mammals contain a testis-specific thioredoxin glutathione reductase (TGR) (Hanschmann et al. 2013). In plant plastids, Trx is reduced by the ferredoxin-thioredoxin reductase (FTR)/ferredoxin system (Meyer et al. 2012) (Fig. 3).
Thioredoxin (TXN), Fig. 3

Catalytic mechanisms of thioredoxins. Trxs can reduce disulfide bridges (A), de-nitrosylate thiols (B shows transnitrosylation), and reduce persulfides (C). In all mechanisms, the N-terminal thiolate of the active site motif starts a nucleophilic attack. The mixed disulfide (A) or the modified cysteine (B, C) is reduced by the C-terminal active site cysteine. The oxidized Trx is reduced by thioredoxin reductase (TrxR) and NADPH or – in plastids – by ferredoxin-thioredoxin reductase (FTR) and ferredoxin (Fdx)

Reduced Trx removes reversible thiol modifications (see 4) (Hanschmann et al. 2013). In the well-described dithiol mechanism, the N-terminal active site cysteine that is characterized by a low pKa value targets the disulfide bond of a substrate via a nucleophilic attack (Fig. 3a). Thereby, a so-called mixed disulfide intermediate is formed between oxidoreductase and substrate, which is reduced by the C-terminal active site cysteine. The substrate leaves the reaction with an altered, reduced redox state, whereas the active site of Trx is oxidized. Trx is also involved in nitric oxide (NO)-mediated signaling cascades. It ameliorates the effects of NO by catalyzing the de-nitrosylation of target cysteine residues (Benhar 2015). Interestingly, nitrosylated small molecular weight thiols react with thiol groups in two ways, leading to transnitrosylation and potentially signal transduction or leading to disulfide formation and release of HNO or NO, potentially promoting or terminating signal transduction. Two mechanisms have been proposed for Trxs that depend on both active site cysteinyl residues: (1) Similar to the dithiol mechanism, the N-terminal active site cysteine attacks the sulfur atom of the nitrosylated thiol, forming a mixed disulfide intermediate, while nitroxyl (NO) is released. In the second step, the C-terminal cysteine reduces the disulfide, releasing the reduced substrate. (2) The N-terminal active site cysteine attacks the nitrogen atom of the nitrosylated thiol, inducing the transnitrosylation (Fig. 3b). The transiently nitrosylated N-terminal cysteine residue is attacked by the C-terminal active site cysteine, leading to disulfide formation and release of NO or NO. As described before, different factors contribute to protein interaction and might influence the site and mode of the attack on nitrosylated targets by Trxs.

In addition, recent data demonstrated that Trx is involved in hydrogen sulfide (H2S) signaling (Mikami et al. 2011). By acting as de-persulfidase, Trx can reduce persulfides from substates such as mercaptopyruvate sulfurtransferase (MST), inducing H2S release. The authors suggested a mechanism similar to the transnitrosylation, introduced above. One of the active site cysteines of Trx attacks the persulfide at the active site Cys247 of MST inducing the transfer of the persulfide. The transient persulfide is then attacked by the other active site cysteine, leading to disulfide formation and release of H2S (Fig. 3c).

Trx can also catalyze the reverse electron flow, leading to the oxidation of particular substrate proteins. One of the main electron acceptors, i.e., oxidants, in cellular signaling is hydrogen peroxide (H2O2). It is important to mention that the second-order rate constants for H2O2 with biomolecules are very low, just about 1 M−1 s−1. In contrast, the catalytic/peroxidatic cysteine residue of Prxs, highly abundant cellular peroxidases of the Trx family, has rate constants of 106–108 M−1 s−1 with H2O2. One of the current models suggests that H2O2 does not directly oxidize proteins, which generally have a significantly lower rate constant including Trx, but is rather sensed by Prxs. These are in turn oxidized and might either transduce the signal directly to target proteins or via the known interaction partner Trx. Obviously, Trx oxidation by Prxs prohibits the interaction with substrates that are generally reduced by Trx (Netto and Antunes 2016). However, it was shown that signaling pathways can be activated by the oxidized Trx such as Ask-A (Hanschmann et al. 2013). In the catalysis of S-nitrosylation, Trx is not directly involved. However, Trx can induce NO production and downstream effects including protein modification by activating NOS activity via de-nitrosylation. Moreover, Trx reduces various nitrosylated low molecular weight thiols including S-nitrosoglutathione.

The enzymatic activity of Trxs is regulated by posttranslational modifications (Fig. 1). Trx was shown to be nitrosylated at the extra cysteinyl residues. Nitrosylation of Cys 69 is essential for redox activity, potentially by preventing the formation of the second disulfide bridge between Cys62 and Cys69 that was described to render the protein enzymatically inactive (Watson et al. 2003), (Hashemy and Holmgren 2008). As another posttranslational modification, S-palmitoylation occurs on Cys73 that also decreases the activity of Trx1 (Xu and Zhong 2015). Human Trx1 only contains one tyrosine residue in position 49 that is critical for protein folding and was shown to be nitrated in the presence of peroxynitrite. This posttranslational modification renders the protein enzymatically inactive, most probably due to conformational changes. Interestingly, the number of tyrosine residues in Trx1 proteins has decreased during evolution. The bacteriophage T4 Trx1 contains five tyrosines, E. coli Trx1 two (Tao et al. 2006).

Functions of Thioredoxin in (Patho)Physiology

The importance of redox regulation and redox signaling is increasingly recognized. Redox regulation describes the control of enzymes and processes by redox modifications, whereas redox signaling is defined as transmission of a redox signal via an essential redox element from a source to a target. Both, redox regulation and signaling, are based on posttranslational reversible oxidative thiol modifications. Cysteine thiols can be glutathionylated or nitrosylated and can form sulfenic acids, persulfides, or disulfides, whereas methionine thiols form R- and S-sulfoxides (Hanschmann et al. 2013). Already in the 1930s, Rapkin described thiol/disulfide changes as regulator of enzymatic activities. The first biological functions characterized as dependent on thiol redox regulation were DNA synthesis, hexose transport, and photosynthesis. Oxidation takes place by reactive oxygen, nitrogen, and sulfur species following, for instance, UV irradiation, hypoxia, and inflammation. Already in 1974, Czech et al. demonstrated that H2O2 can act as second messenger (Czech et al. 1974). However, the acknowledgement of this observation by the scientific community started just a couple of years ago and is still not completed.

As described above, persulfides, disulfides, as well as nitrosylated thiols are reduced by Trxs. Although Trx does not directly remove methionine sulfoxides, it reactivates the specific enzymes, methionine sulfoxide reductases. By these catalytic activities, Trxs modulate enzymatic activities via so-called thiol switches and are in the center of redox regulation and redox signaling (Fig. 4).
Thioredoxin (TXN), Fig. 4

Role of thioredoxin in the concept of redox signaling/redox regulation. Following a specific signal, second messengers such as nitric oxide, hydrogen peroxide, or hydrogen sulfide induce reversible posttranslational thiol modifications. The mechanism of oxidation is not fully understood, but most probably, it is facilitated via enzymes, e.g., peroxiredoxins. Trxs reduce these thiol switches and regulate the specific enzymatic activity of the respective protein. Note that Trxs have also been suggested to be involved in the oxidation of proteins

Trx-dependent physiological functions are, for instance, DNA biosynthesis, transcription, photosynthesis, sulfate assimilation, and protein folding. The importance of the Trx systems for mammals is confirmed by embryonic lethality of mice lacking Trx1, Trx2, TrxR1, or TrxR2. Trx1-deleted mice die early at embryonic day E3.5, Trx2 knockout mice die at the time of mitochondrial maturation during embryonic days E10.5–E12.5, and mice lacking either TrxR1 or TrxR2 die around embryonic days E10 and E14.5, respectively (Hanschmann et al. 2013).

Many pathological conditions are related to modulated expression and activity of Trxs and subsequent changed redox regulation and cell signaling. Trxs, especially Trx1, were investigated in patients, animal models, and cell cultures (Hanschmann et al. 2013). Extracellular Trx has been implicated in the regulation of the immune response. Interestingly, extracellular Trx1 was originally named T-cell leukemia-derived factor. Trx1 levels are increased in blood and cerebrospinal fluid of multiple sclerosis patients, in plasma of myocarditis patients, in blood of patients with chronic heart failure or infectious diseases, as well as in tumor cells. However, not only the protein level is affected, also posttranslational modifications affect Trx1 activity, such as nitration that was observed in hearts of a mouse model for diabetes and led to Trx inhibition. Moreover, changes in tissue distribution and cellular localization related to pathological situations affect functions of Trxs. A dysregulation in the Trx system, i.e., decreased Trx activity and generally elevated levels of thioredoxin-interacting protein (Txnip), the potential endogenous inhibitor of Trx, has been linked to diabetes mellitus.

In most mouse models, increased Trx1 levels were protective against the specific disease. A prominent exception is cancer as Trx1 seems to promote proliferation and survival of tumor cells. So far, the majority of investigations link Trx activity to protection against pathologies and to pathways related to apoptosis, especially to modulation of ASK-1 and NF-κB signaling (Fig. 5).
Thioredoxin (TXN), Fig. 5

Role of thioredoxin during apoptosis. Trx inhibits dissociation of the iκB/NF-κB complex. iκB becomes phosphorylated and degraded by the proteasome; NF-κB translocates into the nucleus. In the nucleus, a cysteine residue of the NF-κB subunit p50 needs to be de-nitrosylated by Trx to allow DNA binding and transcription of specific genes. Transcription of genes dependent on transcription factors activated by p38 or JNK (e.g., c-Jun) is inhibited by binding of reduced Trx to ASK-A and subsequent proteasomal degradation of ASK-A. Oxidized Trx leaves this complex, and ASK-A activates p38 and JNK. Caspase 3, the ultimate protein in induction of apoptosis, is activated by Trx via specific de-nitrosylation


Thioredoxin is an oxidoreductase that regulates protein function via reversible posttranslational modifications at cysteine residues. Thioredoxin is the founding member of the thioredoxin family of proteins that comprises more than 50 members in mammals. Originally, it was described as electron donor for ribonucleotide reductase and as a general antioxidant; today, it has been characterized as specific signaling molecule. Together with NADPH and thioredoxin reductase and in plastids with ferredoxin-thioredoxin reductase and ferredoxin, it forms the so-called thioredoxin system. Knockout of the cytosolic Trx1 or TrxR1, as well as knockout of the mitochondrial Trx2 or TrxR2, is embryonically lethal in mice. Trxs share the common Trx fold and the conserved Cys-Gly-Pro-Cys active site motif. The latter is responsible for the catalysis of disulfide exchange reactions via the dithiol mechanism, as well as protein de-nitrosylation and reduction of protein persulfides. Trx functions in the regulation of specific proteins in complex signaling pathways regulating essential processes such as DNA synthesis, proliferation, differentiation, and apoptosis, as well as cellular responses to environmental changes including hypoxia and inflammation. Mammalian Trx itself is regulated via posttranslational modifications at the three extra cysteine residues and its potential endogenous inhibitor Txnip. Many disorders have been linked to modulated expression and activity of Trxs and Trx family proteins, as well as subsequent modulated redox regulation and cellular signaling.

See Also


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of NeurologyMedical Faculty, Heinrich-Heine University DüsseldorfDüsseldorfGermany