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Thioredoxin Superfamily and Its Effects on Cardiac Physiology and Pathology

Jun Yoshioka

10.1002/cphy.c140042

Source: Volume 5, Issue 2, April 2015

Published online: March 2015

Full Article on Wiley Online Library



ABSTRACT

A precise control of oxidation/reduction of protein thiols is essential for intact cardiac physiology. Irreversible oxidative modifications have been proposed to play a role in the pathogenesis of cardiovascular diseases. An imbalance of redox homeostasis with diminution of antioxidant capacities predisposes the heart to oxidant injury. There is growing interest in endoplasmic reticulum (ER) stress in the cardiovascular field, since perturbation of redox homeostasis in the ER is sufficient to cause ER stress. Because a number of human diseases are related to altered redox homeostasis and defects in protein folding, many research efforts have been devoted in recent years to understanding the structure and enzymatic properties of the thioredoxin superfamily. The thioredoxin superfamily has been well documented as thiol oxidoreductases to exert a role in various cell signaling pathways. The redox properties of the thioredoxin motif account for the different functions of several members of the thioredoxin superfamily. While thioredoxin and glutaredoxin primarily act as antioxidants by reducing protein disulfides and mixed disulfide, another member of the superfamily, protein disulfide isomerase (PDI), can act as an oxidant by forming intrachain disulfide bonds that contribute to proper protein folding. Increasing evidence suggests a pivotal role of PDI in the survival pathway that promotes cardiomyocyte survival and leads to more favorable cardiac remodeling. Thus, the thiol redox state is important for cellular redox signaling and survival pathway in the heart. This review summarizes the key features of major members of the thioredoxin superfamily directly involved in cardiac physiology and pathology. © 2015 American Physiological Society. Compr Physiol 5:513‐530, 2015.

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Figure 1. Figure 1. Architecture of the thioredoxin (Trx) fold in Trx protein. β‐sheet strands are shown as arrows and α‐helices are shown as cylinders. Trx has the common basic Trx fold with an additional β‐sheet (β1') and α‐helix (α1') at the N‐terminus of the protein. Members of the Trx superfamily have an active site containing the Cys‐X‐X‐Cys motif and share the same catalytic mechanism. The Cys‐X‐X‐Cys motif is always located at the N‐terminus of α1 helix.
Figure 2. Figure 2. Architecture of the thioredoxin (Trx) fold in glutaredoxin (Grx) protein. As in Figure 1, β‐sheet strands are shown as arrows and α‐helices are shown as cylinders. Grx has the basic Trx fold only, without any insertion of secondary structure elements. The Trx fold is very versatile, which makes a protein of the Trx superfamily suitable to perform several catalytic functions.
Figure 3. Figure 3. Architecture of the thioredoxin (Trx) fold in the “a” domain of protein disulfide isomerase (PDI) protein. As in Figure 1, β‐sheet strands are shown as arrows and α‐helices are shown as cylinders. PDI has the common basic Trx fold with an additional β‐sheet (β1') and α‐helix (α1') at the N‐terminus of the protein. The PDI “a” domain shares notable features with Trx. In particular, the two active site cysteine residues are in the same position at the N‐terminus of α1helix.
Figure 4. Figure 4. Redox potential of major enzymes of the thioredoxin superfamily. The protein redox potential E0 is based on coupling with the glutathione redox potential (101). Mitochondria and cytosolic compartments are relatively reduced, while the endoplasmic reticulum (ER) is more oxidized. The protein disulfide isomerase (PDI) family normally localizes to the ER compartment and acts as oxidant by forming intrachain disulfide bonds. TrxRD, thioredoxin reductase; Trx, thioredoxin; Grx, glutaredoxin; GSH, reduced glutathione; GR, glutathione reductase.
Figure 5. Figure 5. The thioredoxin (Trx) system. The catalytic active site of Trx includes a Cys‐Gly‐Pro‐Cys motif. These two cysteines (Cys32 and Cys35) are responsible for reducing disulfide bonds of the substrate proteins. The substrate proteins include peroxiredoxins, which reduce H2O2, thereby scavenging redox oxygen species (ROS). Upon transferring the two protons to the substrate protein, Trx becomes oxidized. The oxidized Trx is converted back into the reduced form by Trx reductase (TrxRD) which extracts reducing equivalents from NADPH. Trx1 also interacts with other signaling molecules including nuclear factor κB (NF‐κB), activating protein 1 (AP‐1), and apoptosis signal‐regulating kinase 1 (ASK1).
Figure 6. Figure 6. The thioredoxin (Trx) activity is regulated by posttranslational modifications of cysteine and tyrosine residues in Trx protein. The Cys32‐Gly‐Pro‐Cys35 is the highly conserved active site. Trx contains three other critical cysteine residues at positions 62, 69, and 73, providing the versatile properties of the protein. The Cys62 and Cys69 form a disulfide bond and suppress the activity of Trx. Both Cys69 and Cys73 are the sites of S‐nitrosylation to enhance the Trx activity. The Cys73 undergoes glutathionylation, which inactivate Trx. The Tyr49 has known to be nitrated by peroxynitrite, which irreversibly inactivates Trx.
Figure 7. Figure 7. The glutaredoxin (Grx) system. The catalytic active site of Grx includes a Cys‐Pro‐Tyr‐Cys motif. These two cysteines are responsible for reducing disulfide bonds of the substrate proteins. The substrate proteins include Grx‐dependent peroxiredoxins, which reduce H2O2, thereby scavenging redox oxygen species (ROS). Upon transferring the two protons to the substrate proteins, Grx becomes oxidized. When oxidized, the Grx isoform is regenerated by reduced glutathione (GSH). The resulting oxidized glutathione (GSSG) is in turn reduced by glutathione reductase (GR) at the expense of NADPH.
Figure 8. Figure 8. Schemes for the domain structure of protein disulfide isomerase (PDI), PDIA6, and thioredoxin (Trx). PDI or PDIA6 contains two domains (a and a′) closely similar in their amino acid sequences to that of Trx. The a and a′ domains contain active sites comprising the Cys‐Gly‐His‐Cys motif. The domains b and b′ are structurally similar domains lacking redox activity. The c domain comprises a 24 residue acidic C‐terminal extension in which over half the residues are glutamate or aspartate, followed by a KDEL sequence for retention in the endoplasmic reticulum. The x is an extended linker.
Figure 9. Figure 9. Misfolded proteins accumulate, resulting in endoplasmic reticulum (ER) stress in cardiomyocytes. The protein disulfide isomerase (PDI) family resides in the ER and promotes the proper folding of proteins. PDI transitions from its reduced to oxidized state to drive isomerization of incorrectly formed disulfide bonds in client proteins (right side). PDI can also transition from its oxidized to reduced state to promote disulfide bond formation in client proteins (left side). Thus, PDI is responsible for the appropriate protein folding and suppresses ER stress in cardiomyocytes.
Figure 10. Figure 10. The cardioprotective roles of the thioredoxin superfamily. Production of reactive oxygen species (ROS) is linked to endoplasmic reticulum (ER) stress. Altered redox homeostasis in the ER is sufficient to cause ER stress. Changes in the protein‐folding environment in the ER induce the production of ROS in the ER to cause oxidative stress. Thus, ER stress and oxidative stress coexist in pathologic states, which result in cardiomyocyte apoptosis and eventually lead to the development of cardiac failure. The thioredoxin (Trx) superfamily provides a fundamental defense response to these pathological conditions through multiple mechanisms. Grx, glutaredoxin; PDI, protein disulfide isomerase.


Figure 1. Architecture of the thioredoxin (Trx) fold in Trx protein. β‐sheet strands are shown as arrows and α‐helices are shown as cylinders. Trx has the common basic Trx fold with an additional β‐sheet (β1') and α‐helix (α1') at the N‐terminus of the protein. Members of the Trx superfamily have an active site containing the Cys‐X‐X‐Cys motif and share the same catalytic mechanism. The Cys‐X‐X‐Cys motif is always located at the N‐terminus of α1 helix.


Figure 2. Architecture of the thioredoxin (Trx) fold in glutaredoxin (Grx) protein. As in Figure 1, β‐sheet strands are shown as arrows and α‐helices are shown as cylinders. Grx has the basic Trx fold only, without any insertion of secondary structure elements. The Trx fold is very versatile, which makes a protein of the Trx superfamily suitable to perform several catalytic functions.


Figure 3. Architecture of the thioredoxin (Trx) fold in the “a” domain of protein disulfide isomerase (PDI) protein. As in Figure 1, β‐sheet strands are shown as arrows and α‐helices are shown as cylinders. PDI has the common basic Trx fold with an additional β‐sheet (β1') and α‐helix (α1') at the N‐terminus of the protein. The PDI “a” domain shares notable features with Trx. In particular, the two active site cysteine residues are in the same position at the N‐terminus of α1helix.


Figure 4. Redox potential of major enzymes of the thioredoxin superfamily. The protein redox potential E0 is based on coupling with the glutathione redox potential (101). Mitochondria and cytosolic compartments are relatively reduced, while the endoplasmic reticulum (ER) is more oxidized. The protein disulfide isomerase (PDI) family normally localizes to the ER compartment and acts as oxidant by forming intrachain disulfide bonds. TrxRD, thioredoxin reductase; Trx, thioredoxin; Grx, glutaredoxin; GSH, reduced glutathione; GR, glutathione reductase.


Figure 5. The thioredoxin (Trx) system. The catalytic active site of Trx includes a Cys‐Gly‐Pro‐Cys motif. These two cysteines (Cys32 and Cys35) are responsible for reducing disulfide bonds of the substrate proteins. The substrate proteins include peroxiredoxins, which reduce H2O2, thereby scavenging redox oxygen species (ROS). Upon transferring the two protons to the substrate protein, Trx becomes oxidized. The oxidized Trx is converted back into the reduced form by Trx reductase (TrxRD) which extracts reducing equivalents from NADPH. Trx1 also interacts with other signaling molecules including nuclear factor κB (NF‐κB), activating protein 1 (AP‐1), and apoptosis signal‐regulating kinase 1 (ASK1).


Figure 6. The thioredoxin (Trx) activity is regulated by posttranslational modifications of cysteine and tyrosine residues in Trx protein. The Cys32‐Gly‐Pro‐Cys35 is the highly conserved active site. Trx contains three other critical cysteine residues at positions 62, 69, and 73, providing the versatile properties of the protein. The Cys62 and Cys69 form a disulfide bond and suppress the activity of Trx. Both Cys69 and Cys73 are the sites of S‐nitrosylation to enhance the Trx activity. The Cys73 undergoes glutathionylation, which inactivate Trx. The Tyr49 has known to be nitrated by peroxynitrite, which irreversibly inactivates Trx.


Figure 7. The glutaredoxin (Grx) system. The catalytic active site of Grx includes a Cys‐Pro‐Tyr‐Cys motif. These two cysteines are responsible for reducing disulfide bonds of the substrate proteins. The substrate proteins include Grx‐dependent peroxiredoxins, which reduce H2O2, thereby scavenging redox oxygen species (ROS). Upon transferring the two protons to the substrate proteins, Grx becomes oxidized. When oxidized, the Grx isoform is regenerated by reduced glutathione (GSH). The resulting oxidized glutathione (GSSG) is in turn reduced by glutathione reductase (GR) at the expense of NADPH.


Figure 8. Schemes for the domain structure of protein disulfide isomerase (PDI), PDIA6, and thioredoxin (Trx). PDI or PDIA6 contains two domains (a and a′) closely similar in their amino acid sequences to that of Trx. The a and a′ domains contain active sites comprising the Cys‐Gly‐His‐Cys motif. The domains b and b′ are structurally similar domains lacking redox activity. The c domain comprises a 24 residue acidic C‐terminal extension in which over half the residues are glutamate or aspartate, followed by a KDEL sequence for retention in the endoplasmic reticulum. The x is an extended linker.


Figure 9. Misfolded proteins accumulate, resulting in endoplasmic reticulum (ER) stress in cardiomyocytes. The protein disulfide isomerase (PDI) family resides in the ER and promotes the proper folding of proteins. PDI transitions from its reduced to oxidized state to drive isomerization of incorrectly formed disulfide bonds in client proteins (right side). PDI can also transition from its oxidized to reduced state to promote disulfide bond formation in client proteins (left side). Thus, PDI is responsible for the appropriate protein folding and suppresses ER stress in cardiomyocytes.


Figure 10. The cardioprotective roles of the thioredoxin superfamily. Production of reactive oxygen species (ROS) is linked to endoplasmic reticulum (ER) stress. Altered redox homeostasis in the ER is sufficient to cause ER stress. Changes in the protein‐folding environment in the ER induce the production of ROS in the ER to cause oxidative stress. Thus, ER stress and oxidative stress coexist in pathologic states, which result in cardiomyocyte apoptosis and eventually lead to the development of cardiac failure. The thioredoxin (Trx) superfamily provides a fundamental defense response to these pathological conditions through multiple mechanisms. Grx, glutaredoxin; PDI, protein disulfide isomerase.
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Article Title: Thioredoxin Superfamily and Its Effects on Cardiac Physiology and Pathology
 

How to Cite

Jun Yoshioka. Thioredoxin Superfamily and Its Effects on Cardiac Physiology and Pathology. Compr Physiol 2015, 5: 513-530. doi: 10.1002/cphy.c140042