Regulation of Annexin A2 by Reversible Glutathionylation

The annexin A2-S100A10 heterotetramer (AIIt) is a multifunctional Ca2+-dependent, phospholipid-binding, and F-actin-binding phosphoprotein composed of two annexin A2 subunits and two S100A10 subunits. It was reported previously that oxidative stress from exogenous hydrogen peroxide or generated in response to tumor necrosis factor-α results in the glutathionylation of Cys8 of annexin A2. In this study, we demonstrate that AIIt is an oxidatively labile protein whose level of activity is regulated by the redox status of its sulfhydryl groups. Oxidation of AIIt by diamide resulted in a time- and concentration-dependent loss of the ability of AIIt to interact with phospholipid liposomes and F-actin. The inhibitory effect of diamide on the activity of AIIt was partially reversed by dithiothreitol. In addition, incubation of AIIt with diamide and GSH resulted in the glutathionylation of AIIt in vitro. Mass spectrometry established the incorporation of 2 mol of GSH/mol of annexin A2 subunit at Cys8 and Cys132. Glutathionylation potentiated the inhibitory effects of diamide on the activity of AIIt. Furthermore, AIIt could be deglutathionylated by glutaredoxin (thiol transferase). Thus, we show for the first time that AIIt can undergo functional reactivation by glutaredoxin, therefore establishing that AIIt is regulated by reversible glutathionylation. The annexin A2-S100A10 heterotetramer (AIIt) is a multifunctional Ca2+-dependent, phospholipid-binding, and F-actin-binding phosphoprotein composed of two annexin A2 subunits and two S100A10 subunits. It was reported previously that oxidative stress from exogenous hydrogen peroxide or generated in response to tumor necrosis factor-α results in the glutathionylation of Cys8 of annexin A2. In this study, we demonstrate that AIIt is an oxidatively labile protein whose level of activity is regulated by the redox status of its sulfhydryl groups. Oxidation of AIIt by diamide resulted in a time- and concentration-dependent loss of the ability of AIIt to interact with phospholipid liposomes and F-actin. The inhibitory effect of diamide on the activity of AIIt was partially reversed by dithiothreitol. In addition, incubation of AIIt with diamide and GSH resulted in the glutathionylation of AIIt in vitro. Mass spectrometry established the incorporation of 2 mol of GSH/mol of annexin A2 subunit at Cys8 and Cys132. Glutathionylation potentiated the inhibitory effects of diamide on the activity of AIIt. Furthermore, AIIt could be deglutathionylated by glutaredoxin (thiol transferase). Thus, we show for the first time that AIIt can undergo functional reactivation by glutaredoxin, therefore establishing that AIIt is regulated by reversible glutathionylation. The molecular mechanisms by which the cell alleviates oxidative stress and achieves redox homeostasis are still a matter of considerable debate. However, the modulation of the thiol disulfide status of critical cysteine residues on proteins is being recognized as a critical mechanism of oxidative signal transduction as well as a cellular response to protect key regulatory molecules from oxidative insult (1Zheng M. Aslund F. Storz G. Science. 1998; 279: 1718-1721Crossref PubMed Scopus (957) Google Scholar, 2Barrett W.C. DeGnore J.P. Konig S. Fales H.M. Keng Y.F. Zhang Z.Y. Yim M.B. Chock P.B. Biochemistry. 1999; 38: 6699-6705Crossref PubMed Scopus (428) Google Scholar, 3Klatt P. Lamas S. Eur. J Biochem. 2000; 267: 4928-4944Crossref PubMed Scopus (653) Google Scholar). Recent evidence suggests that the reversible covalent modification of cysteine residues by the tripeptide glutathione (γ-Glu-Cys-Gly) plays a significant role in the antioxidant network of the cells and is involved in regulating individual aspects of cellular function (3Klatt P. Lamas S. Eur. J Biochem. 2000; 267: 4928-4944Crossref PubMed Scopus (653) Google Scholar, 4Schafer F.Q. Buettner G.R. Free Radic. Biol. Med. 2001; 30: 1191-1212Crossref PubMed Scopus (3551) Google Scholar). Although proteins can bind cysteine, GSH, and homocysteine to generate mixed disulfides, GSH is the dominant ligand, as it occurs in the cell at concentrations between 1 and 10 mm (5Smith C.V. Jones D.P. Guenthner T.M. Lash L.H. Lauterburg B.H. Toxicol. Appl. Pharmacol. 1996; 140: 1-12Crossref PubMed Scopus (280) Google Scholar, 6Seres T. Ravichandran V. Moriguchi T. Rokutan K. Thomas J.A. Johnston Jr., R.B. J. Immunol. 1996; 156: 1973-1980PubMed Google Scholar). S-Glutathionylation has been shown to alter the function of a number of discrete proteins under oxidant stress (7Cotgreave I.A. Gerdes R.G. Biochem. Biophys. Res. Commun. 1998; 242: 1-9Crossref PubMed Scopus (430) Google Scholar, 8Fratelli M. Demol H. Puype M. Casagrande S. Eberini I. Salmona M. Bonetto V. Mengozzi M. Duffieux F. Miclet E. Bachi A. Vandekerckhove J. Gianazza E. Ghezzi P. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 3505-3510Crossref PubMed Scopus (481) Google Scholar). Furthermore, the formation of a mixed disulfide with glutathione precludes the irreversible oxidation of the cysteine thiol to a sulfinic or sulfonic acid and enables reactivation of the protein by cellular thioreductases. Annexins compose a large multigene family of water-soluble proteins that can bind to negatively charged phospholipids and cellular membranes in a Ca2+-dependent fashion (9Moss S.E. Trends Cell Biol. 1997; 7: 87-89Abstract Full Text PDF PubMed Scopus (67) Google Scholar, 10Raynal P. Pollard H.B. Biochim. Biophys. Acta. 1994; 1197: 63-93Crossref PubMed Scopus (1020) Google Scholar, 11Swairjo M.A. Seaton B.A. Annu. Rev. Biophys. Biomol. Struct. 1994; 23: 193-213Crossref PubMed Scopus (186) Google Scholar). The annexin family is structurally characterized by two domains: a highly conserved α-helical protein core consisting of four 70-amino acid repeats (eight repeats in the case of annexin VI) and a variable N-terminal segment (12Gerke V. Moss S.E. Physiol. Rev. 2002; 82: 331-371Crossref PubMed Scopus (1596) Google Scholar). Annexin A2 is unique among the annexins, for its N-terminal tail possesses a high affinity binding site for a dimeric protein (monomeric Mr 11,000), S100A10 (13Waisman D.M. Mol. Cell. Biochem. 1995; 149/150: 301-322Crossref Scopus (259) Google Scholar). Annexin A2 can thus exist as a monomer or as its heterotetrameric complex ((annexin A2)2-(S100A10)2), known as the annexin A2-S100A10 heterotetramer (AIIt). 1The abbreviations used are: AIIt, annexin A2-S100A10 heterotetramer; DTT, dithiothreitol; glutathione 1The abbreviations used are: AIIt, annexin A2-S100A10 heterotetramer; DTT, dithiothreitol; glutathione Annexin A2 has been shown previously to and membranes PubMed Scopus Google Scholar, Biochem. J. PubMed Scopus Google Scholar, Biochim. Biophys. Acta. 1995; J. PubMed Scopus Google and AIIt has been as a between the and T. K. J. Cell Biol. PubMed Scopus Google Scholar, T. T. M. H. Cell Res. 1994; PubMed Scopus Google Scholar). to the that annexin A2 and AIIt are involved in regulating as and in D.M. Mol. Cell. Biochem. 1995; 149/150: 301-322Crossref Scopus (259) Google Scholar). In to phospholipid binding a number of been as Ca2+-dependent F-actin-binding proteins (12Gerke V. Moss S.E. Physiol. Rev. 2002; 82: 331-371Crossref PubMed Scopus (1596) Google Scholar). The of cells has a role in as and cellular Cell Biol. 1994; PubMed Scopus Google Scholar, Science. PubMed Scopus Google Scholar). Furthermore, the in signal transduction that cell and and 1997; PubMed Scopus Google Scholar, T. E. G. J. Cell 2000; PubMed Scopus Google Scholar, J. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). Annexin A2 can bind and possesses a Ca2+-dependent activity in its heterotetrameric (9Moss S.E. Trends Cell Biol. 1997; 7: 87-89Abstract Full Text PDF PubMed Scopus (67) Google Scholar, D.M. Mol. Cell. Biochem. 1995; 149/150: 301-322Crossref Scopus (259) Google Scholar). has shown previously that the F-actin-binding site can be to the of annexin as of the acid residues of the binding activity of annexin A2 and AIIt D.M. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). Annexin A2 was as an protein in It was shown that oxidant stress from exogenous or generated in response to tumor necrosis factor-α incorporation of a glutathione the cysteine of the annexin A2 N-terminal D.M. T. Biochemistry. 2000; PubMed Scopus Google Scholar). In addition, and Biochem. Biophys. 2000; PubMed Scopus Google and and P. Biochemistry. 2002; PubMed Scopus Google that modification of AIIt by the sulfhydryl or by with results in a loss of activity in vitro. Although annexin A2 has been in been of the role cysteine residues in the activity of the In this study, we show for the first time that AIIt is an oxidatively labile protein whose level of activity is regulated by the redox status of its sulfhydryl groups. that glutathionylation of AIIt in results in the modification of Cys8 and of the annexin A2 subunit and results in the of the phospholipid and binding activity of AIIt. However, of AIIt by glutaredoxin AIIt results that the of annexin A2 a role in the of the of the protein and can be regulated by reversible glutathionylation. was from as by H.M. G. S.E. D.M. Biochemistry. 1997; PubMed Scopus Google Scholar). glutaredoxin (thiol was by J. A2 and A2 from was from and was from was from hydrogen diamide tumor necrosis and from in was from was from of Annexin the for annexin A2 the that at and of annexin A2 of the by cells and as previously M. Zhang D.M. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). proteins as previously M. Zhang D.M. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). of of annexin A2 and S100A10 at for and at for 1 and the of the heterotetramer was from the individual subunits by in mm mm mm and mm at of was to a of and D.M. T. Biochemistry. 2000; PubMed Scopus Google Scholar). a of mm in mm was a of in to a of The was at was to a of and the was at for 1 glutathione was by the with for 1 at with The was and the of the was to and an in mm The was with and with The with in glutathione at and the was in a The was with in at the was a and the of thiol was Mass molecular of or AIIt was by spectrometry on a 2 to AIIt was annexin A2 and S100A10 subunits and on a mm The annexin A2 subunit was and mm and was was to for 10 or at of the was with 10 mm The 2 with a high was used to by spectrometry was the from Science. for Free The for is on the of with formation of the of acid is with in mm in a of was at an The results to a generated glutathione as the of and and AIIt, annexin and S100A10 under to oxidation of cysteine of AIIt by AIIt was with GSH and diamide in at for 2 diamide and GSH by an of AIIt was by incubation of AIIt with mm GSH and glutaredoxin in at and with to and to a at for 1 The was with in 10 mm and mm for 1 at and for 1 at with A2 or or 2 in with The was with and at with a of in with In the case of the was with in with the the was with and of and in by The was in 1 of phospholipid mm and 2 mm and at for with a to generate phospholipid at a of 1 was in a at in a of phospholipid and phospholipid in a phospholipid of the of AIIt or annexin A2 to the for 10 are as the of AIIt and are as as previously H.M. G. S.E. D.M. Biochemistry. 1997; PubMed Scopus Google Scholar). the of AIIt the of phospholipid at 10 by AIIt was as phospholipid the was at in a The used in the from to The was in of and for The was by and with was as previously J.A. PubMed Scopus Google Scholar). was by the to the in a as previously D.M. J. Biol. Full Text PDF PubMed Google Scholar). The and at with and was in mm and mm and was to the to a of was by the of AIIt to a of a incubation at was in at the the was at for 10 in a The was in of and for The was by and with binding was as that the was the incubation the was at for in a The was first in of mm for and of the was for The was by concentrations and the concentrations to as by Biochem. PubMed Scopus Google Scholar). used or of Annexin is a of glutathione that was to incorporation of glutathione proteins to oxidative It has been previously that two proteins of cells and annexin A2 D.M. T. Biochemistry. 2000; PubMed Scopus Google Scholar). the of this cells as a shown in oxidant stress from exogenous hydrogen peroxide an in the incorporation of a large number of cellular Furthermore, of proteins with resulted in the loss of the establishing that proteins However, of cells with hydrogen peroxide alter the cellular protein of annexin A2 we the cells to hydrogen peroxide and the proteins from the cellular by with by with The proteins by and annexin A2 was by shown in of cells with hydrogen peroxide resulted in the of annexin A2 in the protein that of the cells to hydrogen peroxide the incorporation of the glutathione annexin therefore the that annexin A2 oxidative stress D.M. T. Biochemistry. 2000; PubMed Scopus Google Scholar). AIIt to is a highly thiol oxidant that molecules as glutathione M.A. PubMed Scopus Google Scholar, M. F. G. J. A. J. 1998; PubMed Scopus Google Scholar). However, diamide can of The that AIIt is in suggests that AIIt be to sulfhydryl the of AIIt to thiol oxidation by the activity of AIIt with a of the activity of AIIt, we the well characterized ability of AIIt to phospholipid in a Ca2+-dependent in V. Moss S.E. Physiol. Rev. 2002; 82: 331-371Crossref PubMed Scopus (1596) Google and D.M. J. and Google Scholar). shown in 2 and diamide the activity of AIIt in a time- and concentration-dependent of AIIt activity at mm and at 2 mm the activity was by the oxidation of AIIt by diamide was shown in incubation of AIIt with 2 mm diamide resulted in a significant loss of protein and this loss could be partially reversed by In of AIIt with mm diamide resulted in a loss of the ability of to the activity of the suggests that the of the activity of AIIt by diamide oxidation of sulfhydryl it was partially reversed by The of to of the activity of AIIt at diamide concentrations suggests that the protein could be by results demonstrate that oxidation of AIIt by diamide a loss of AIIt activity and that can partially this diamide therefore be the activity of AIIt by disulfide formation between the subunits of AIIt or between the two molecules of AIIt. the of diamide be to the of and AIIt was shown in diamide of AIIt resulted in a in the of the protein as well as the formation of The in the and of AIIt was reversed the protein was with that diamide the oxidation of AIIt and the formation of disulfide between AIIt diamide the binding of AIIt to the phospholipid the was and the AIIt was by of AIIt to the phospholipid that oxidation of AIIt by diamide resulted in a loss of the ability of AIIt to bind to the phospholipid Furthermore, incubation of the protein with of AIIt It has been shown previously that annexin A2 in a Ca2+-dependent in D.M. J. Biol. Full Text PDF PubMed Google Scholar, Jr., M.A. J. Cell Biol. PubMed Scopus Google Scholar). Recent established that the of the annexin A2 subunit of AIIt an F-actin-binding the acid residues of the of the annexin A2 subunit to be for the binding activity of AIIt D.M. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). Ca2+-dependent binding to AIIt annexin and D.M. J. Biol. Full Text PDF PubMed Google Scholar). used to the ability of AIIt to shown in oxidation of AIIt by diamide resulted in a loss of of partially reversed the oxidative effects of 1 mm to the oxidative effects of mm that the in was to a loss of formation of of we of the that at that the which of and AIIt, can be at this shown in the formation of the by AIIt was and partially we or the of activity by AIIt was to binding of F-actin. the ability of AIIt to bind to high F-actin-binding proteins with F-actin. shown in oxidation of AIIt resulted in a loss of binding which was partially reversed by However, mm diamide AIIt. Thus, concentrations of diamide the irreversible oxidation of AIIt and the loss of the phospholipid and binding activity of the AIIt by that AIIt is by diamide is with the that AIIt is to glutathionylation in However, we could the effect of glutathionylation on the activity of AIIt, we to generate of the protein in a we AIIt with glutathione and diamide and the by an to shown in the formation of a mixed disulfide between glutathione and the annexin A2 incubation of AIIt with the to resulted in the of glutathione we that AIIt was AIIt was to The molecular of the S100A10 subunit to be and for the and it was that S100A10 was The molecular of the annexin A2 subunit was to be with for the protein and a molecular of for this in molecular of that annexin A2 subunit been by 2 mol of of annexin A2 was by the number of in AIIt. by the an loss of between AIIt and AIIt was the in annexin AIIt and annexin A2 to and the by of the annexin A2 subunit has been reported to in the of the protein a acid N-terminal and a core protein D.M. J. and Google Scholar). The N-terminal a shown in the molecular of the N-terminal by of the protein was with an molecular of for the The in molecular of is with the of glutathione on the of the with the resulted in a in the molecular from to with the of the at we a of the annexin A2 subunit and the by as The first the that Cys8 as a The as a the established that Cys8 and in the N-terminal and annexin are in vitro. of AIIt by that thiol oxidation of AIIt by diamide the phospholipid activity of the protein and that 1 mm diamide an of AIIt activity by incubation of AIIt with 1 mm diamide and 2 mm a protein with 2 mol of of annexin A2 subunit was shown in at the of AIIt used in activity AIIt was suggests that glutathione the inhibitory effect of diamide on the activity of the concentrations of AIIt used in the activity could be the that glutathionylation of AIIt resulted in an in the for we the activity of the protein with shown in the to the activity of the that glutathionylation of AIIt alter the for Although the glutathionylation of AIIt its it was this a reversible mechanism for the of irreversible we the effect of of glutathione on AIIt of proteins results in the of we the effect of on the activity of AIIt. shown in incubation of AIIt with the with of AIIt activity being in (thiol is a well characterized that in to by glutathione as an is therefore a critical of the cellular that to and the glutathionylation of protein in therefore the that AIIt is a of shown in incubation of AIIt with glutaredoxin and glutathione resulted in the of AIIt activity reported that incubation of AIIt with results in the of the binding of AIIt to phospholipid E. P. P. D.M. Eur. J. Biochem. 2002; PubMed Scopus Google Scholar). However, as shown in AIIt to bind to phospholipid Furthermore, incubation of AIIt with glutaredoxin resulted in the of the inhibitory effects of results demonstrate that AIIt can be and that glutathionylation of AIIt the ability of the protein to bind to and Glutathionylation the of AIIt with the ability of AIIt to shown in AIIt a in activity as by In incubation of AIIt with 1 mm diamide resulted in a loss of of the activity of AIIt suggests that glutathione the inhibitory effect of diamide on the activity of AIIt. Furthermore, we that incubation of AIIt with or glutaredoxin of of the activity of the protein that the in was to a loss of formation of the used in the by shown in the formation of the by AIIt was and glutaredoxin partially this we or the of activity by AIIt was to a binding affinity for F-actin. shown in AIIt of the binding activity of AIIt. Furthermore, incubation of AIIt with resulted in the of the binding activity of AIIt. of in and results show that glutathionylation of Cys8 and of the annexin A2 subunit of AIIt results in a loss of and binding it or of for the of AIIt, we to the protein of two AIIt and AIIt by of the annexin A2 subunits with the S100A10 subunit and the that the AIIt of its activity However, incubation of this with diamide resulted in a loss of which was by incubation of the protein with in to are involved in the loss of AIIt The to the AIIt suggests that this cysteine plays a key role in the reactivation of the the AIIt of its The of this was a loss of we to the role that plays in the loss of activity of AIIt. of mixed between glutathione and in proteins has been known to oxidative stress in 3Klatt P. Lamas S. Eur. J Biochem. 2000; 267: 4928-4944Crossref PubMed Scopus (653) Google Scholar, I.A. Gerdes R.G. Biochem. Biophys. Res. Commun. 1998; 242: 1-9Crossref PubMed Scopus (430) Google Scholar, and Free Radic. Res. 1999; PubMed Scopus Google Scholar). protein glutathionylation has as a of redox of protein Thus, glutathionylation can the of redox as well as protein from irreversible oxidative Glutathionylation in the of protein as has been reported for proteins as or for as the activity with glutathionylation M. Demol H. Puype M. Casagrande S. Eberini I. Salmona M. Bonetto V. Mengozzi M. Duffieux F. Miclet E. Bachi A. Vandekerckhove J. Gianazza E. Ghezzi P. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 3505-3510Crossref PubMed Scopus (481) Google Scholar). Although the of reported an of activity by it that the of the cysteine modification is in the effect of glutathionylation. 1 can be or by glutathionylation on which cysteine is involved K. J. Fales H.M. Biochemistry. 1996; PubMed Scopus Google are glutathionylation of the T. T. T. A. H. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). In this study, we the that oxidative stress of cells results in the glutathionylation of the annexin A2 subunit of AIIt. the that AIIt be regulated by an oxidative mechanism D.M. T. Biochemistry. 2000; PubMed Scopus Google Scholar). shown that AIIt is an oxidatively labile protein whose level of activity is in by the redox status of its sulfhydryl groups. Oxidation of AIIt by diamide results in a loss of the ability of AIIt to interact with phospholipid liposomes and F-actin. Furthermore, glutathionylation of AIIt the inhibitory effects of diamide and the of AIIt with phospholipid liposomes and F-actin. AIIt can be deglutathionylated by Thus, we shown for the first time that AIIt can undergo functional reactivation by AIIt is a protein that is composed of two annexin A2 and two S100A10 subunits in V. Moss S.E. Physiol. Rev. 2002; 82: 331-371Crossref PubMed Scopus (1596) Google Scholar, D.M. J. and Google Scholar, and D.M. J. and Google Scholar, F. Cell 1999; PubMed Scopus Google Scholar, B.A. 1998; PubMed Scopus Google Scholar). The of annexin A2 to be with S100A10 as AIIt. The annexin A2 subunit is a with and The the and the and The the and the and of the The of binding for D.M. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google G. D.M. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google and G. A. P. D.M. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). The N-terminal the binding site for the S100A10 which is a of the family of proteins J. Biochem. Cell Biol. 2001; PubMed Scopus Google Scholar). Annexin A2 cysteine and Cys8 and are on the in the and is the at which this a disulfide in M. Zhang D.M. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The of and are it has been on that residues a disulfide in the annexin A2 monomer A. S. J. A. P. V. J. K. J. Mol. Biol. 1996; PubMed Scopus Google Scholar). In Cys8 has been well has been shown to be a thiol that is in and that with homocysteine and in D.M. T. Biochemistry. 2000; PubMed Scopus Google Scholar, Biochem. Biophys. 2000; PubMed Scopus Google Scholar, J. Med. 1998; Google Scholar). Biochim. Biophys. Acta. PubMed Scopus Google the of diamide with a of sulfhydryl and that the of diamide with glutathione has the among of the sulfhydryl is the thiol in the diamide glutathione to in a and Furthermore, diamide with a thiol as GSH a protein thiol GSH is 1995; PubMed Scopus Google Scholar). results in the of diamide with an protein However, glutathione and diamide are in the with annexin glutathione with an glutathione can with a protein sulfhydryl to annexin A2. The of AIIt with diamide and glutathione resulted in the incorporation of 2 mol of of annexin A2 by spectrometry that Cys8 and to mixed with The loss of AIIt activity was by the of DTT, by the mixed In addition, AIIt was by the glutaredoxin (thiol the that the of AIIt is a is the first of the of AIIt activity by reversible glutathionylation. proteins can be by with a the formation of this from It was that incubation of AIIt with a results in a loss of by AIIt E. P. P. D.M. Eur. J. Biochem. 2002; PubMed Scopus Google Scholar). However, it was established in a disulfide is with AIIt. the that the glutathionylation of AIIt be to the acid cell The mechanism by which glutathionylation the activity of AIIt is It is that the glutathionylation of Cys8 and the sulfhydryl and its function as a in the cellular is that the in AIIt and a in the In of this is of the of or of annexin which results in the of a to a loss of AIIt activity I. D.M. J. Biol. 267: Full Text PDF PubMed Google Scholar, I. Jones J. S. D.M. Biochemistry. 1995; PubMed Scopus Google Scholar). it is that of the glutathione annexin A2 a of the of the in a loss of The role that glutathionylation of AIIt plays in is the redox status of the of AIIt to be an of phospholipid and it is that glutathionylation to protect residues from irreversible oxidative cysteine residues are to the acid acid can with glutathione to the mixed The acid can to its irreversible sulfinic and sulfonic acid it is to a and reversible as the that diamide can and AIIt suggests that diamide can Cys8 and to the acid and to the sulfinic acid Glutathionylation of the acid therefore the protein from oxidation to its irreversible and thus an mechanism for the of AIIt the of or glutathionylation is critical for of AIIt we and the to phospholipid In addition, the of this a loss of α-helical that this is Although the to the we the effect of diamide on the and annexin A2 we that the phospholipid activity of the was by diamide suggests that plays an role in the of annexin A2 to oxidation or that of results in a in annexin A2 that results in loss of diamide It is therefore or this plays a role in the of the activity of the The glutathionylation of AIIt be a molecular mechanism which oxidation can in protein and therefore a for redox of AIIt as a of redox of its to a reversible mixed disulfide with protein that glutaredoxin reversible of AIIt. therefore that the of AIIt be regulated by redox

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.