Peptide Switch Is Essential for Sirt1 Deacetylase Activity

SummaryIn mammals, the Sirtuins are composed of seven Sir2 orthologs (Sirt1–7) with a conserved deacetylase core that utilizes NAD+ as a cofactor. Interestingly, the deacetylase core of Sirt1 by itself has no catalytic activity. We found within the C-terminal domain a 25 aa sequence that is essential for Sirt1 activity (ESA). Our results indicate that the ESA region interacts with and functions as an “on switch” for the deacetylase core. The endogenous Sirt1 inhibitor DBC1, which also binds to the deacetylase core, competes with and inhibits the ESA region from interacting with the deacetylase core. We discovered an ESA mutant peptide that can bind to the deacetylase core and inhibit Sirt1 in trans. By using this mutant peptide, we were able to inhibit Sirt1 activity and to increase the chemosensitivity of androgen-refractory prostate cancer cells. Therefore, the ESA region is a potential target for development of therapies to regulate Sirt1.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (114 K)Download as PowerPoint slideHighlights► The ESA region in the C-terminal domain is essential for Sirt1 activity ► The ESA region confers activity by interacting with the Sirtuin domain ► The ESA region increases Sirt1-substrate interaction ► Mutant ESA peptide inhibits Sirt1 and increases chemosensitivity in tumor cells