Research in the Bothner lab has two main focuses: (1) Investigation of cellular response to stress using chemical biology, proteomics, and metabolomics. (2) Assembly, stability, and dynamics of multi-subunit enzymes and nucleoprotein complexes.
This research takes us from the atomic scale provided by high resolution structural models of viruses and enzymes to complex interaction networks of nucleic acids, metabolites, and proteins that make up a living system. A diverse set of analytical, biophysical, biochemical, and chemical biology techniques are used in the discovery process. The Bothner lab is part of the Biological Electron Transfer and Catalysis (BETCy) Energy Frontiers Research Center (EFRC), the Thermal Biology Institute, and MSU’s new Keck program in Extreme Microbiology of Yellowstone.
(1) Cellular response to stress (such as temperature, oxygen, pH, and viral infection) involves numerous networks and signaling pathways. We measure changes in protein abundance and activity along with metabolomics perturbations to elucidate the pathways and networks that control biology. Activity based protein profiling (ABPP) is a method that has been developed to address the activity level of proteins on a global scale and constitutes a new strategy for functional proteomics. Leading edge mass spectrometry and more recently NMR are the pillar of our omics investigations. A wide range of projects spanning extremophiles in Yellowstone National Park, response of human the microbiome to arsenic, and hemorrhagic shock are ongoing.
(2) Nature has evolved active bio-architectures that are both dynamic and responsive. Protein function is intimately connected to dynamics; therefore, knowledge of the frequency, range, and coordination of motion in large complexes is critical to understanding biological mechanisms. We use protein cages as a paradigm for studying the assembly and protein dynamics important to the function of supramolecular complexes. On-going projects include use of adeno associated virus (AAV) in targeted gene therapy, the role of protein dynamics in gene editing by CRISPR complexes, and the mechanism of action behind small molecule Hepatitis B antivirals, and enzyme complexes using electron bifurcation.