We are interested in how internal cellular organization is generated, maintained and remodeled. Microtubules and the motors that move along them are essential for these processes. Our research efforts are focused on cytoplasmic dynein, a microtubule-based molecular motor that transports dozens of different cargoes in mammalian cells, including nuclei and other organelles, viruses, mRNAs and signaling molecules. Dynein also plays a critical role in cell division.

Because dynein functions in so many basic biological processes it is not surprising that mutations in dynein or dynein-associated proteins cause human disease. For example, mutations in some dynein-associated proteins cause a brain developmental defect called lissencephaly, while mutations in other dynein-associated proteins have been found in several human cancers. We are interested in understanding the molecular basis of dynein’s role in these disease states.

Cytoplasmic dynein is arguably the most challenging and understudied cytoskeletal motor protein. Understanding how dynein works as a molecular machine has been challenging due to its size and many associated subunits. Using S. cerevisiae, we created the first genetically tractable biochemical source of dynein, allowing us to create recombinant forms of the complex and begin to dissect its mechanism. Using this system we performed single molecule biophysical experiments that led us to propose a model for how an individual dynein molecule takes consecutive steps along its microtubule track. The ability to introduce any desired alteration, such as disease point mutations, into the complete dynein complexes we purify places us in a unique position to continue to dissect the dynein mechanism.

In S. cerevisiae there are 11 known dynein associated proteins, all of which are required for dynein function in vivo. These proteins are all functionally conserved in other eukaryotes. In addition to our interest in unraveling the dynein mechano-chemical cycle, another current focus of the lab is to determine what role these dynein-associated proteins have in dynein motor activity, ATPase activity, and cargo association.