Understanding the redox activity of Sestrin-family proteins
Sestrins are a family of stress-inducible proteins found in most animal species. Even though anti-aging function of Sestrins has been well documented through extensive genetic studies, the molecular and biochemical nature of Sestrins was elusive due to the lack of structural studies. Recently, we have determined the crystal structure of Sestrin2, and shown that Sestrin is a structural homologue of bacterial oxidoreductase family named AhpD (alkylhydroperoxidase D). Through in vitro studies, we have shown that Sestrins can indeed function as a oxidoreductase for hydrophobic ROS, such as alkylhydroperoxides. In this project, we will comprehensively investigate the redox-regulating activity of Sestrin-family proteins through an interdisciplinary approach combining genetic studies in Sestrins-deficient mouse and fly strains, mass spectrometry-based oxidative proteomics, and structure-guided biochemical analyses.