Reversible Sequestration of Active Site Cysteines in a 2Fe-2S-bridged Dimer Provides a Mechanism for Glutaredoxin 2 Regulation in Human Mitochondria

Human mitochondrial glutaredoxin 2 (GLRX2), which controls intracellular redox balance and apoptosis, exists in a dynamic equilibrium of enzymatically active monomers and quiescent dimers. Crystal structures of both monomeric and dimeric forms of human GLRX2 reveal a distinct glutathione binding mode and show a 2Fe-2S-bridged dimer. The iron-sulfur cluster is coordinated through the N-terminal active site cysteine, Cys-37, and reduced glutathione. The structures indicate that the enzyme can be inhibited by a high GSH/GSSG ratio either by forming a 2Fe-2S-bridged dimer that locks away the N-terminal active site cysteine or by binding non-covalently and blocking the active site as seen in the monomer. The properties that permit GLRX2, and not other glutaredoxins, to form an iron-sulfur-containing dimer are likely due to the proline-to-serine substitution in the active site motif, allowing the main chain more flexibility in this area and providing polar interaction with the stabilizing glutathione. This appears to be a novel use of an iron-sulfur cluster in which binding of the cluster inactivates the protein by sequestering active site residues and where loss of the cluster through changes in subcellular redox status creates a catalytically active protein. Under oxidizing conditions, the dimers would readily separate into iron-free active monomers, providing a structural explanation for glutaredoxin activation under oxidative stress. Human mitochondrial glutaredoxin 2 (GLRX2), which controls intracellular redox balance and apoptosis, exists in a dynamic equilibrium of enzymatically active monomers and quiescent dimers. Crystal structures of both monomeric and dimeric forms of human GLRX2 reveal a distinct glutathione binding mode and show a 2Fe-2S-bridged dimer. The iron-sulfur cluster is coordinated through the N-terminal active site cysteine, Cys-37, and reduced glutathione. The structures indicate that the enzyme can be inhibited by a high GSH/GSSG ratio either by forming a 2Fe-2S-bridged dimer that locks away the N-terminal active site cysteine or by binding non-covalently and blocking the active site as seen in the monomer. The properties that permit GLRX2, and not other glutaredoxins, to form an iron-sulfur-containing dimer are likely due to the proline-to-serine substitution in the active site motif, allowing the main chain more flexibility in this area and providing polar interaction with the stabilizing glutathione. This appears to be a novel use of an iron-sulfur cluster in which binding of the cluster inactivates the protein by sequestering active site residues and where loss of the cluster through changes in subcellular redox status creates a catalytically active protein. Under oxidizing conditions, the dimers would readily separate into iron-free active monomers, providing a structural explanation for glutaredoxin activation under oxidative stress. Glutaredoxins (GLRXs) 4The abbreviations used are: GLRX, glutaredoxin; MES, 2-morpholinoethane-sulfonic acid. are evolutionarily conserved, glutathione-dependent oxidoreductases that are critically involved in the maintenance of cellular redox homeostasis (1Holmgren A. Johansson C. Berndt C. Lonn M.E. Hudemann C. Lillig C.H. Biochem. Soc. Trans. 2005; 33: 1375-1377Crossref PubMed Scopus (362) Google Scholar, 2Holmgren A. J. Biol. Chem. 1989; 264: 13963-13966Abstract Full Text PDF PubMed Google Scholar). The enzymes belong to the thioredoxin-fold superfamily of proteins and catalyze a broad spectrum of thiol-disulfide reactions using two distinct reaction mechanisms that require either 1 or 2 cysteines in a Cys-X-X-Cys active site motif. Reduction of protein and low molecular weight disulfides proceeds through a dithiol mechanism that results in an intramolecular disulfide that is reduced by two molecules of glutathione through a glutathione-protein mixed disulfide intermediate. In contrast, glutathionylation and deglutathionylation reactions require only the more N-terminal cysteine. In these reactions, a GLRX-glutathione mixed disulfide occurs that is either formed or reduced by one molecule of glutathione (1Holmgren A. Johansson C. Berndt C. Lonn M.E. Hudemann C. Lillig C.H. Biochem. Soc. Trans. 2005; 33: 1375-1377Crossref PubMed Scopus (362) Google Scholar). To date, three low molecular weight GLRXs with 15–34% sequence identity and distinct active site motifs have been described in mammalian cells. The well studied cytosolic glutaredoxin 1 (GLRX1) is a 12-kDa protein that contains the classical Cys-Pro-Tyr-Cys motif. GLRX1 supplies electrons to ribonucleotide reductase, catalyzes disulfide-dithiol exchanges in proteins or small molecules such as dehydroascorbate, and is intimately involved in transcriptional regulation, cellular differentiation, and apoptotic processes (1Holmgren A. Johansson C. Berndt C. Lonn M.E. Hudemann C. Lillig C.H. Biochem. Soc. Trans. 2005; 33: 1375-1377Crossref PubMed Scopus (362) Google Scholar). Glutaredoxin 2 (GLRX2) is a 16-kDa protein directed either to the nucleus or to the mitochondria through differential splicing of the first exon (3Lundberg M. Johansson C. Chandra J. Enoksson M. Jacobsson G. Ljung J. Johansson M. Holmgren A. J. Biol. Chem. 2001; 276: 26269-26275Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar). Human GLRX2 contains a 37CSYC40 active site motif with a serine residue replacing the conserved proline and has several biochemical properties that distinguish it from GLRX1, perhaps as a result of this substitution (4Johansson C. Lillig C.H. Holmgren A. J. Biol. Chem. 2004; 279: 7537-7543Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). First, GLRX2 catalyzes more efficiently monothiol-mediated protein deglutathionylation reactions due to its high affinity for glutathione-protein mixed disulfides and has been shown to catalyze the reversible glutathionylation of complex I and other proteins in the inner mitochondrial membrane (5Beer S.M. Taylor E.R. Brown S.E. Dahm C.C. Costa N.J. Runswick M.J. Murphy M.P. J. Biol. Chem. 2004; 279: 47939-47951Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar). Second, GLRX2 is not inhibited by oxidation of structural cysteine residues (3Lundberg M. Johansson C. Chandra J. Enoksson M. Jacobsson G. Ljung J. Johansson M. Holmgren A. J. Biol. Chem. 2001; 276: 26269-26275Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar). Third, in addition to receiving reducing equivalents from glutathione, GLRX2 can also receive electrons from thioredoxin reductase (4Johansson C. Lillig C.H. Holmgren A. J. Biol. Chem. 2004; 279: 7537-7543Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). More recently glutaredoxin 5 (GLRX5), with only one cysteine residue in the active-site motif, has been characterized in the yeast Saccharomyces cerevisiae, with homologs found in organisms from bacteria to humans (6Wingert R.A. Galloway J.L. Barut B. Foott H. Fraenkel P. Axe J.L. Weber G.J. Dooley K. Davidson A.J. Schmid B. Paw B.H. Shaw G.C. Kingsley P. Palis J. Schubert H. Chen O. Kaplan J. Zon L.I. Nature. 2005; 436: 1035-1039Crossref PubMed Scopus (326) Google Scholar, 7Rodriguez-Manzaneque M.T. Ros J. Cabiscol E. Sorribas A. Herrero E. Mol. Cell. Biol. 1999; 19: 8180-8190Crossref PubMed Scopus (265) Google Scholar, 8Molina-Navarro M.M. Casas C. Piedrafita L. Belli G. Herrero E. FEBS Lett. 2006; 580: 2273-2280Crossref PubMed Scopus (69) Google Scholar, 9Belli G. Polaina J. Tamarit J. De La Torre M.A. Rodriguez-Manzaneque M.T. Ros J. Herrero E. J. Biol. Chem. 2002; 277: 37590-37596Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar). It is of particular interest that GLRX5 is targeted to mitochondria like GLRX2 and that GLRX5 participates in the biogenesis of iron-sulfur clusters (10Rodriguez-Manzaneque M.T. Tamarit J. Belli G. Ros J. Herrero E. Mol. Biol. Cell. 2002; 13: 1109-1121Crossref PubMed Scopus (395) Google Scholar, 11Tamarit J. Belli G. Cabiscol E. Herrero E. Ros J. J. Biol. Chem. 2003; 278: 25745-25751Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). An alignment of these three human isoforms is provided in Fig. 1. Previous experimental results provide substantial evidence for a critical role of GLRX2 as a sensor of the mitochondrial redox status. The small interfering RNA-mediated down-regulation of mitochondrial GLRX2 resulted in dramatically increased sensitivity toward apoptotic stimuli such as doxorubicin or phenylarsine oxide (12Lillig C.H. Lonn M.E. Enoksson M. Fernandes A.P. Holmgren A. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 13227-13232Crossref PubMed Scopus (135) Google Scholar), whereas overexpression of GLRX2 prevented cardiolipin oxidation, cytochrome c release, and induction of apoptosis (13Enoksson M. Fernandes A.P. Prast S. Lillig C.H. Holmgren A. Orrenius S. Biochem. Biophys. Res. Commun. 2005; 327: 774-779Crossref PubMed Scopus (145) Google Scholar). Importantly, mitochondrial GLRX2 exists in two distinct states in vivo: the catalytically competent monomeric form and a recently discovered inactive dimeric state that contains an iron-sulfur cluster. Under conditions of oxidative stress, there is a transition from the inactive dimer to active monomeric GLRX2 initiated by decreased GSH/GSSG ratios (14Lillig C.H. Berndt C. Vergnolle O. Lonn M.E. Hudemann C. Bill E. Holmgren A. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 8168-8173Crossref PubMed Scopus (241) Google Scholar). In this instance, loss of the cluster through change of the redox status creates a catalytically active protein. An in-depth spectroscopic characterization of dimeric human GLRX2 by Lillig et al. (14Lillig C.H. Berndt C. Vergnolle O. Lonn M.E. Hudemann C. Bill E. Holmgren A. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 8168-8173Crossref PubMed Scopus (241) Google Scholar) identified the presence of Fe(III) in tetrahedral sulfur coordination and additional parameters consistent with a [2Fe-2S]2+ cluster coordinated by 4 cysteine residues. The same study determined the stoichiometry to be two iron and two sulfide atoms per dimer, suggesting that the cluster served to mediate dimerization. However, there are conflicting reports of the residues responsible for coordinating the iron-sulfur cluster. Based upon mutagenic data, it was proposed that 2 cysteines outside the active site coordinate the cluster (14Lillig C.H. Berndt C. Vergnolle O. Lonn M.E. Hudemann C. Bill E. Holmgren A. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 8168-8173Crossref PubMed Scopus (241) Google Scholar). In contrast, Feng et al. (15Feng Y. Zhong N. Rouhier N. Hase T. Kusunoki M. Jacquot J.P. Jin C. Xia B. Biochemistry. 2006; 45: 7998-8008Crossref PubMed Scopus (95) Google Scholar) presented NMR data suggesting that poplar glutaredoxin C1 coordinates an iron-sulfur cluster through the N-terminal active-site cysteines and two glutathione molecules. We have determined the crystal structures of human GLRX2 in monomeric and dimeric forms, which reveal novel details of glutathione binding and provide clear proof for iron coordination through 2 active-site cysteines. Expression, Purification, and Characterization of Recombinant Human GLRX2—A template plasmid encoding for full-length human GLRX2 was obtained from Invitrogen. Two constructs lacking the N-terminal mitochondrial targeting sequence (comprising GLRX2 core residues 56–164 and 41–164) were cloned into pNic28-Bsa4, a pET21a-derived expression vector with a tobacco etch virus cleavable N-terminal His6 tag. Since the length of the mature protein after mitochondrial import is unknown, two clones were constructed. The shorter clone was designed to coincide with the N terminus of human GLRX1, whereas the longer construct (containing an additional 15 amino acids) corresponds to a clone used in previous biophysical characterization (3Lundberg M. Johansson C. Chandra J. Enoksson M. Jacobsson G. Ljung J. Johansson M. Holmgren A. J. Biol. Chem. 2001; 276: 26269-26275Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar, 14Lillig C.H. Berndt C. Vergnolle O. Lonn M.E. Hudemann C. Bill E. Holmgren A. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 8168-8173Crossref PubMed Scopus (241) Google Scholar). Expression plasmids were transformed into a phage-resistant derivative of BL21(DE3) carrying a plasmid for rare codon expression. Protein expression was induced by adding 1 mm isopropyl-1-thio-β-d-galactopyranoside to cultures grown in TB (Terrific Broth) medium to A600 = 3.4, and then cultures were further incubated at 18 °C overnight. Cell pellets were resuspended in 50 mm potassium phosphate buffer, pH 7.5, 500 mm NaCl, 10 mm imidazole, protease inhibitors (Complete, Sigma) and lysed using a high pressure homogenizer. Cell debris and nucleic acids were removed by the addition of 0.15% polyethyleneimine followed by centrifugation for 30 min at 40,000 × g, and the supernatant was further clarified by filtration. The proteins were purified using nickel-affinity chromatography (GE Healthcare), and monomeric and dimeric GLRX2 were separated by gel filtration chromatography with a Superdex 200 column (GE Healthcare) equilibrated in 10 mm HEPES, pH 7.5, 500 mm NaCl, and 5% glycerol. Eluted proteins were analyzed by SDS-PAGE and concentrated in an Amicon 5K centrifugal concentrator. Monomeric and dimeric GLRX2 were analyzed by UV-visible spectroscopy (Labtech, Nanodrop 1000 spectrophotometer), and the molecular mass was verified by electrospray mass ionization-time-of-flight mass spectrometry (Agilent LC/MSD time-of-flight). Aerobic Crystallization of Reduced Monomeric GLRX2 in Complex with Glutathione—Reduced glutathione to a final concentration of 10 mm was added to the dimeric fraction of GLRX2Δ1–55 to in the form of were grown by at °C in a of 50 of protein and of pH The crystal was to a from with in Crystallization of dimeric GLRX2 with an for was purified as described 10 mm reduced glutathione and were and with (14Lillig C.H. Berndt C. Vergnolle O. Lonn M.E. Hudemann C. Bill E. Holmgren A. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 8168-8173Crossref PubMed Scopus (241) Google Scholar). The protein was concentrated to and under of 1 of protein and 1 of well was equilibrated well mm MES, pH in a under to oxidation of the iron-sulfur cluster. Under these conditions, and to a of crystal was to a of pH in and was the crystal grown to the atoms and data for monomeric and dimeric crystal forms of GLRX2 were at the the were by molecular using A.J. Biol. 2004; PubMed Scopus Google Scholar) and the from the NMR H. and S. The dimeric crystal form was by molecular using and the from the data with and atoms In both 5% of the data were for of for the final which are the result of of and with the P. K. Biol. 2004; PubMed Scopus Google Scholar) and Biol. PubMed Scopus Google Scholar), are in data and in are for data in GLRX2 GLRX2 Cell c atoms length in a The for monomeric GLRX2 protein one glutathione and molecules. The for the dimeric form protein residues an two glutathione and molecules. residues are in and additional of a by R.A. J. Google Scholar). The protein residues in the are to be consistent with previous and are residues from the provide into glutathione binding and coordination of the iron-sulfur cluster in human GLRX2, have both monomeric and dimeric forms of the protein in the presence of reduced glutathione. Two of GLRX2, the core sequence the mitochondrial targeting were and constructs and the additional residues at the N terminus of the longer construct were and not in the were by mass the presence of one intramolecular disulfide Monomeric and dimeric GLRX2 were separated by gel filtration chromatography and analyzed by spectroscopy one of analyzed SDS-PAGE of that the of was the monomeric The dimeric fraction of GLRX2 was and at and consistent with protein an iron-sulfur complex (14Lillig C.H. Berndt C. Vergnolle O. Lonn M.E. Hudemann C. Bill E. Holmgren A. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 8168-8173Crossref PubMed Scopus (241) Google Scholar). that were grown at a in with the presence of to the fraction from gel filtration chromatography were it was that the dimer into monomers of Monomeric Human resulted in of the dimeric GLRX2 to a reduced in complex with glutathione. GLRX2 the of the thioredoxin a mixed GLRX2 contains 4 in two that are in to The first is reduced and is in the conserved motif that is to be involved in The forms a disulfide and is the of the molecule away from the This is conserved in GLRX2 proteins and not found in GLRX1 or GLRX5 enzymes Importantly, the formed these residues likely protein by the and this disulfide an explanation GLRX2 is to oxidation of structural cysteines (3Lundberg M. Johansson C. Chandra J. Enoksson M. Jacobsson G. Ljung J. Johansson M. Holmgren A. J. Biol. Chem. 2001; 276: 26269-26275Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar) there are cysteines to further the of human GLRX2 was determined by NMR and with crystal in complex with that the in the This contains the N-terminal the are likely due to glutathione is to the active site of the GLRX2 monomer. The glutathione into a the of GLRX2, and residue in the glutathione several polar with the protein The forms with of and as well as the of The cysteine main chain has two with the and of and the is in polar with the of and In the of the glutathione the of and there are three molecules the and protein. the glutathione is in a where it form a disulfide with the the the sulfur atoms is that this is likely to be the sulfur atoms in the structural disulfide is in this would from binding under reducing conditions and the with human GLRX1 (3Lundberg M. Johansson C. Chandra J. Enoksson M. Jacobsson G. Ljung J. Johansson M. Holmgren A. J. Biol. Chem. 2001; 276: 26269-26275Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar). This binding also be the for the affinity of GLRX2 for a that GLRX2 from other M. Holmgren A. Johansson M. Protein Expression 2006; 45: PubMed Scopus Google Scholar). of the Protein for with a glutathione the three human glutaredoxin 1 Y. S. S. J. Biochemistry. PubMed Scopus Google Scholar), glutaredoxin 1 P. Xia O. Holmgren A. M. K. J. Mol. Biol. PubMed Scopus Google Scholar), and E. glutaredoxin K. Berndt M. T. H. H. G. Holmgren A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). are NMR structures of a glutathione-protein mixed disulfide with the N-terminal cysteine in the motif. the E. this is the main interaction glutathione and the has two additional polar the glutathione to a and the glutathione cysteine to a of human GLRX1 Y. S. S. J. Biochemistry. PubMed Scopus Google Scholar) and GLRX2 that the interaction the glutathione and the is interaction occurs in this and in GLRX1, the glutathione only with the chain of the in binding the two human structures is that the of glutathione is with the in the GLRX1 an in the other glutaredoxin structural is for the active-site GLRX5 or of its GLRX5 has only a cysteine in its active-site motif, it has been shown to have reductase J. Belli G. Cabiscol E. Herrero E. Ros J. J. Biol. Chem. 2003; 278: 25745-25751Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar), and it has been further that a cysteine, is for the in GLRX2, the residue to in human to a the of GLRX2 to the active that the reaction for GLRX5 likely proceeds through a dithiol mechanism with the residue outside the classical Cys-X-X-Cys active-site motif. of GLRX2 a [2Fe-2S]2+ GLRX2 dimer is of two GLRX2 protein an and 2 glutathione molecules The cysteine has been proposed to mediate by coordinating the iron-sulfur cluster for the this is not conserved in other only GLRX2 is to form an iron-sulfur-containing dimer, and of these residues dimer expression (14Lillig C.H. Berndt C. Vergnolle O. Lonn M.E. Hudemann C. Bill E. Holmgren A. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 8168-8173Crossref PubMed Scopus (241) Google Scholar). In to this the dimeric crystal that the cluster is coordinated through Cys-37, the N-terminal cysteine in the active-site motif. the cluster is iron is coordinated by Cys-37, two sulfur and a cysteine by glutathione. The two both iron atoms to the of and the cluster is The chain a high one of the cluster from and from oxidative the glutathione to the it as the polar with the protein are and additional are found with the protein In the glutathione molecule with chain additional are found with the main chain and the chain A. The for glutathione with chain is in an where it its with and whereas the cysteine sulfur forms an additional with the of chain B. of the chain of is not only to the cluster also it forms additional with the glutathione from the monomer. It is likely that a proline at this as occurs in GLRX1, cluster coordination by reducing the flexibility of the protein and the proline chain would not be to form with the glutathione of role of mitochondrial GLRX2 is not at the the crystal structures several Previous (12Lillig C.H. Lonn M.E. Enoksson M. Fernandes A.P. Holmgren A. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 13227-13232Crossref PubMed Scopus (135) Google Scholar, 14Lillig C.H. Berndt C. Vergnolle O. Lonn M.E. Hudemann C. Bill E. Holmgren A. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 8168-8173Crossref PubMed Scopus (241) Google Scholar) have that GLRX2 is in mitochondrial redox An GLRX2 mitochondria toward oxidative and apoptosis (12Lillig C.H. Lonn M.E. Enoksson M. Fernandes A.P. Holmgren A. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 13227-13232Crossref PubMed Scopus (135) Google Scholar), that GLRX2 be an in for for apoptotic It is that GLRX2 has several due to its in glutathionylation and deglutathionylation In the protein are in concentration of protein are for oxidative and as a are Costa N.J. Dahm C.C. S.M. Brown S.E. A. Murphy M.P. 2005; PubMed Scopus Google Scholar). It is likely that GLRX2 has a role in by the further of GLRX2 is that it appears to be to enzymatically under oxidative First, high GSH/GSSG ratios the GLRX2 equilibrium into a quiescent dimeric form (12Lillig C.H. Lonn M.E. Enoksson M. Fernandes A.P. Holmgren A. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 13227-13232Crossref PubMed Scopus (135) Google Scholar, 14Lillig C.H. Berndt C. Vergnolle O. Lonn M.E. Hudemann C. Bill E. Holmgren A. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 8168-8173Crossref PubMed Scopus (241) Google Scholar), which can readily be as as the GSH/GSSG ratio under oxidative Second, appears to be a as by the complex of monomeric GLRX2 with reduced glutathione. Third, of other GLRX2 can be reduced by thioredoxin reductase (4Johansson C. Lillig C.H. Holmgren A. J. Biol. Chem. 2004; 279: 7537-7543Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar), a role under increased oxidative stress. It that this of GLRX2 through into a dimeric state and by with its is of for mitochondrial further are to the role of GLRX2 in mitochondrial redox and to with other mitochondrial such as which has also been shown to be involved in mitochondrial redox P. K. C. J. Biochem. 2001; PubMed Scopus Google Scholar, A. Biophys. PubMed Scopus Google Scholar, N. Mol. Cell Biol. 2005; PubMed Scopus Google Scholar). particular can electrons to GLRX2 P. E. Johansson C. Holmgren A. Biochem. Biophys. Res. Commun. 2002; PubMed Scopus Google Scholar), a or its and GLRX2 in redox GLRX2 is likely in mechanisms as mitochondrial oxidative and redox are to and 2005; PubMed Scopus Google Scholar, N. Y. Acad. Sci. 2006; PubMed Scopus (135) Google Scholar, P. Sci. 2006; Scholar). It is to that of GLRXs and it be that GLRX2 has a in iron-sulfur cluster as has been recently shown for GLRX5 (6Wingert R.A. Galloway J.L. Barut B. Foott H. Fraenkel P. Axe J.L. Weber G.J. Dooley K. Davidson A.J. Schmid B. Paw B.H. Shaw G.C. Kingsley P. Palis J. Schubert H. Chen O. Kaplan J. Zon L.I. Nature. 2005; 436: 1035-1039Crossref PubMed Scopus (326) Google Scholar). GLRX2 is the first of the mitochondrial to have its crystal and it would be to and the with the active site GLRX5 that is involved in the and of cluster in in a biochemical study the structural in this study GLRX2 coordination E. and C. H. with the and as well as data by is The is a by the the of the the and the for the and and the with

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