Structural Biology of Signal Transduction

Research in my laboratory focuses on important problems in signal transduction pertinent to human health. Our approach is interdisciplinary, combining, biochemical, biophysical, cell biological and molecular biology methods to gain insight into the mechanisms governing signal transduction in eukaryotic and prokaryotic systems. The major goal is to elucidate the molecular mechanisms that regulate signal transduction. Our recent work has focused on two systems.

The first system involves understanding the fundamental role of protein motions or “dynamics” in allostery. We use a number of model systems to understand how binding of a ligand at one site is influenced by residues at a distal site. Our recent work has focused on PDZ domains, which are abundant peptide-binding domains in eukaryotic and prokaryotic organisms. The PDZ domains of interest are derived from eukaryotic signal transduction proteins (e.g., Tiam1 guanine nucleotide exchange factor, CASK kinase) and have been linked to disease. We use computer simulations, biochemical experiments, and biophysical techniques to elucidate how allostery is transmitted within PDZ domains and how mutations disrupt this allostery. More recently, we have used computational tools to design artificial PDZ domains with the goal of using these systems to reveal how allostery is encoded within the PDZ domain to regulate ligand binding. Finally, we collaborate with biologists to assess how allosteric regulation of ligand binding impacts the in vivo function.

The second system centers on Staphylococcus aureus two-component signal transduction (TCS) systems that sense and respond to environmental signals to allow bacteria to adapt to a wide range of environmental niches. TCSs are comprised of a sensory histidine kinase that senses the environmental signal and a response regulator protein that responds is phosphorylated by the HK to induce changes in gene expression. Our recent work has focused on understanding the mechanisms by which histidine kinases (HK) sense and transduce signals into conformational changes that regulate enzyme activity and biological function of the TCS. We use structural biology tools [X-ray crystallography, nuclear magnetic resonance (NMR), and cryogenic electron microscopy (Cryo-EM)], biophysical tools and biochemistry to elucidate the mechanisms of regulation. In addition, we collaborate with biologists to connect the insights determined from biophysics to the biology of pathogenesis.