Chemical Biology of Protein Lipidation
Our group has developed a series of molecular imaging reagents that report on APTs, protein lipidation “eraser” enzymes, in live human cells. We have used these molecules to discover that APT activities are not static, but respond dynamically to varied cellular input signals, such as growth factor signaling. Using targeted probes, we discovered that mitochondria house APTs, including a previously unrecognized role for APT1, the foundational member of this class of signaling enzymes. Finally, we discovered a new member of the APT family of regulatory proteins, which we characterized through biochemical, structural, and cell biological experimentation, and discovered this new APT regulates mitochondrial redox signaling through its S-depalmitoylation activity.
Our chemical technologies. We have developed two approaches for engineering small molecule probes to measure endogenous APT activity, turn-on (left panel, DPPs) and ratiometric (right panel, RDPs) probes. These tools are enabling us to explore new types of biology.
More recently, we have begun to shift our attention to the DHHC "writer" proteins, developing a new class of acrylamide-based inhibitors. We are interested in pursing more potent and selective chemical probes for these important families of protein lipidation regulatory systems.