Our ongoing research can be divided into the following two areas:
A. Chemical Biology
We continue to develop new chemical approaches to dissect dynamic cellular processes. For example, we are developing potent and selective chemical probes for proteins in the AAA+ (ATPases associated with diverse cellular activities) family. To validate these inhibitors we are applying DrugTargetSeqR, an approach that combines genomics with chemical biology to identify physiological targets of chemical inhibitors. We are also using chemical proteomics to profile post-translational modification-dependent protein-protein interactions required for error-free cell division and genome stability.
Drugs targeting many of the proteins we study are in clinical trials as anti-cancer agents and our work sheds light on how these drugs work. The chemical inhibitors we identify to examine cellular mechanisms can also provide starting points for developing new chemotherapeutic agents.
B. Unraveling Cellular Mechanisms
We are working to reconstitute a ‘minimal’ cell division apparatus with purified proteins. These studies are providing insight into how essential proteins can be regulated by simple geometric features, which can be ~1000-fold larger than the proteins themselves. Such geometric features include the lengths of microtubules or their overlap. The principles of dynamic self-assembly that we uncover by studying the microtubule-based structures needed for error-free cell division are likely to be general and can help explain the assembly of other complex cellular architectures, such as those needed for directional transport in neurons. In order to firmly link findings from these biochemical and biophysical studies to cell biology, we are validating chemical probes and using state-of-the-art microscopy methods (e.g. lattice light sheet microscopy).