We use a variety of techniques including X-ray crystallography to discover at the molecular level how proteins function, how they are regulated, and to unlock the mechanism underlying their function. We are interested in the structure, function, and assembly of protein-protein and protein-DNA interactions. We have an active research interest in several areas:
Eukaryotic gene transcription is an essential and highly regulated process that is dependent on a large set of protein factors centered around the enzyme RNA polymerase II (Pol II). The Paf1 complex (Pol II Associated Factor 1) is a 5-subunit transcription elongation factor, conserved from yeast to humans, that travels with the elongating polymerase and is required for the maintenance of histone modifications, the recruitment of RNA processing factors and the communication with transcriptional activators. Mutation or deletion of Paf1C subunits is associated with a variety of cancers, including leukemia and parathyroid tumors, underscoring its biological importance. How the Paf1 complex coordinates its many activities is unknown. Our work is focused on understanding the architecture and function of this complex.
Temperate bacteriophages usually form lysogens, where the prophage genome is integrated into (or excised from) the host chromosome by an array of proteins, most notably the phage-encoded integrases. We are looking to understand how serine-integrases, which have unusually large and complex DNA binding domains, recognize their DNA targets and direct the integration mechanism. Additionally, we are interested in understanding the structural differences between the integration and excision synaptic complexes. We are studying this through an exploration of novel Xis proteins which are protein factors that bend DNA and direct the formation of the excisive synaptic complex.
Defects in neural tube closure during development are among the most common of birth defects, striking about 1 in 1,000 live births. The actin-binding protein Shroom is essential for neural tube closure in a variety of vertebrate organisms by establishing an actomyosin network at the apical surface of polarized epithelial cells, and through the process of apical constriction inducing changes in cell shape that facilitate development. A novel domain at the C-terminus of Shroom, called SD2, is required for apical constriction. We are looking to discover the mechanism by which the SD2 domain interacts with its binding partner Rho-kinase to facilitate apical constriction.
