Protein acetylation is one of the most frequent post-translational modifications in the human proteome and orchestrates diverse cellular processes. Further, dysregulation of protein acetylation is associated with a broad range of disease, ranging from cancer and neurological disease to immunological disorders. Despite this importance, current strategies to investigate protein acetylation directly in cells are often non-specific or lack temporal and magnitude control. In this seminar, I will present our lab’s efforts to address these challenges through the development of a chemistry-centric method, called AceTAG, to induce acetylation of targeted proteins. The AceTAG system utilizes bifunctional small molecules to induce proximity between the lysine acetyltransferase p300/CBP and proteins genetically tagged with the small protein tag FKBP12<sup>F36V</sup>, resulting in their acetylation. Using AceTAG, we demonstrate that p300/CBP can be recruited directly to tagged proteins resulting in their targeted acetylation at functionally relevant sites in cells. We demonstrate AceTAG-mediated acetylation is dose-controlled, reversible, rapid, and selective for tagged protein targets. Moreover, I will present compelling evidence that AceTAG is a useful tool to illuminate the functional consequences of acetylation. Looking forward, we envision that AceTAG will enable broader investigations into protein acetylation and will facilitate the exploration of targeted acetylation in therapeutic contexts.

AceTAG: A heterobifunctional molecule system for targeted protein acetylation in cells

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.