Action and Regulation of Sirtuin Proteins
Recent estimates indicate that the human genome only contains ~19,000 protein encoding genes, or slightly less than the nematode worm genome. Protein post-translational modification is largely responsible for the complexity arising from the small number of genes that humans possess. The Smith lab focuses on the post-translational modification of critical charged and nucleophilic residues by lysine acylation and cysteine S-nitrosation.
Post-translational modification of histones, transcription factors, and other nuclear proteins forms the basis of epigenetics and regulates transcription through unknown mechanisms. The combinatorial effect of these post-translational modifications underlies the “histone language” that is interpreted by three broad protein classes: “writers”, “readers”, and “erasers”. Lysine residues are particularly abundant targets of epigenetic regulation and are modified by an astounding array of modifications including methylation, ubiquitinylation, sumoylation, ADP-ribosylation, oxidation, and acylation. One focus of my laboratory will be on the mechanism and regulation of the sirtuin family of proteins that erase and read sites of epigenetic lysine acylation.
The pharmaceutical industry is intensely interested in developing sirtuin activators for the treatment of a variety of aging-associated diseases including cancer, type II diabetes, and neurodegenerative disorders. However, existing activators of the human sirtuin, Sirt1, act through unknown mechanisms. In this project area, the lab seeks to investigate the binding sites and activation mechanisms of Sirt1 activators using hydrogen-deuterium exchange mass spectrometry. Additionally, Sirt1 is inactivated by cysteine S-nitrosation, but the mechanism of inactivation is unknown. The mechanism of Sirt1 inactivation by S-nitrosation will be determined. The lab seeks to also investigate potential sites of post-translational modification in other sirtuin family proteins.
© 2017 Brian Smith Lab
Department of Biochemistry
Medical College of Wisconsin
8701 Watertown Plank Rd,
Milwaukee, WI, 53226 | (414) 955-5659