Protein S-glutathionylation is a chemical post-translational modification characterized by the formation of protein-glutathione mixed disulfides. This protein modification is dependent on the intracellular redox status and our hypothesis is that protein S-glutathionylation would have a modulatory function upon the activity of particular proteins and so, would promote alterations in the cellular response in order to recover / protect cells from oxidative damage. We have previously demonstrated that the catalytic unit of the intracellular protease, namely proteasome 20S, is prone to S-glutathionylation what modifies two site specific proteasomal activities beside of increasing the rates of degradation of oxidized proteins, an important finding related to the physiological role of this process. We also showed that proteasomal S-glutathionylation is reversed by oxidoreductases (glutaredoxins and thioredoxins). In a recent report we showed that the oligopeptidase EP24.15, responsible for the degradation of peptides generated by the 20S proteasome, among other physiological functions, is in vitro as well as in vivo S-glutathionylated. Moreover, it was verified that EP24.15 S-glutathionylation modulates its activity and induces its oxidative oligomerization. To continue further in this topic, our basic goals in the present project are to characterize (1) the structural modifications related to alterations of kinetic parameters and to the opening of the catalytic chamber of the S-glutathionylated proteasome 20S; (2) the functional role of proteasome S-glutathionylation in dendritic cells (generation of peptidic fragments utilized for the antigen presentation through MHC type I complexes); (3) the functional role of the oligopeptidase EP24.15 S-glutathionylation and, (4) structural features of EP24.15 that induce its S-glutathionylation and subsequent oligomerization (aminoacid residues; possible motives and domains). (AU)
Articles published in Agência FAPESP Newsletter about the research grant:
SILVA, GUSTAVO M.;
NETTO, LUIS E. S.;
SANTOS, LUIZ F. A.;
GOZZO, FABIO C.;
DEMASI, MARCOS A. A.;
OLIVEIRA, CRISTIANO L. P.;
BICEV, RENATA N.;
KLITZKE, CLECIO F.;
SOGAYAR, MARI C.;
Redox Control of 20S Proteasome Gating.
Antioxidants & Redox Signaling,
Web of Science Citations: 47.
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