Jonathan Willett successfully defends PhD thesis
Monday, November 19, 2012
Jonathan Willett successfully defended his PhD thesis, "Bacterial Two-Component Systems Share a Common Mechanism to Regulate Signaling and Specificity," on Monday, November 19, 2012.
Despite years of intensive research, many of the fundamental aspects of two-component signal transduction pathways are not yet understood. Interestingly these systems are found throughout all domains of life including archaea, bacteria and eukaryotes and are known to regulate diverse cellular processes such as motility, pathogenesis, development, biofilm formation, and toxin production. Despite many groups working on two-component systems it is not yet appreciated whether these systems have conserved features, amino acid requirements, structures and specificity. By understanding the mechanisms by which signals propagate through these systems we could perhaps develop novel therapeutics targeting these pathways.
In order to address these questions my thesis has focused on studying the signaling pathways which regulate multicellular development in the model soil bacterium Myxococcus xanthus. The developmental process is highlighted by large changes in gene expression patterns and motility resulting in the production of large macroscopic fruiting bodies composed of metabolically dormant myxospores. My initial work focused on characterizing the Che3 chemosensory pathway known to regulate time of aggregation required for fruiting body formation. I discovered an additional kinase CrdS which works with the Che3 system to regulate phosphorylation of the important developmental regulator CrdA.
Additionally I performed mutagenesis on the kinase CrdS to demonstrate that specific residues in CrdS are required for both kinase and phosphatase activities. A conserved Thr/Asn was required for phosphatase activity while a conserved acidic residue was required for kinase activity. Importantly, these residues are highly conserved and when we made mutations in multiple other kinases, we saw similar requirements, indicating the importance of these residues.
Further analysis focused on 26 other CrdA homologs found within the M. xanthus genome. Using phosphotransfer profiling and a newly created phosphatase profiling method we were able to demonstrate signaling specificity whereby each kinase was able to phosphorylate and dephosphorylate a single response regulator. Since phosphotransfer and phosphatase activities are predicated upon protein-protein interactions, we also determined that cognate pairs exhibited preferential binding. Cumulatively this research highlights a conserved mechanism governing the signal transduction pathways regulating multicellular development in M. xanthus.
Jonathan hails from Bloomington, Indiana, which is known for two things, basketball and Jonathan Willett. A product of his proud parents, Tom and Karen Willett, Jonathan grew up always the envy of his younger brother Jesse. During high school Jonathan developed an interest in Microbiology and started working in the lab of Dr. Carl Bauer at Indiana University. Jonathan continued working in Dr. Bauer’s Lab throughout his undergraduate years where he was able to travel to two international conferences and publish several scientific articles on his research. With the encouragement from his undergraduate mentor, Jonathan came to the University of Iowa in the Fall of 2007 to start work in the lab of Dr. John Kirby.
During his time at Iowa, Jonathan had the opportunity to spend two summers being Dr. Kirby’s assistant instructor for the Advanced Bacterial Genetics Course at Cold Spring Harbors Labs. Additionally, Jonathan was able to attend multiple conferences to present his working, including his favorite one in Cuernavaca, Mexico. His research at Iowa has resulted in several first author papers including an article just accepted in PLoS Genetics title “Genetic and Biochemical Dissection of a HisKA Domain Identifies Residues Required Exclusively for Kinase and Phosphatase Activities”. Upon graduation Jonathan will move with his wife Carlie to the University of Chicago where he will start a postdoctoral fellowship, in the lab of Dr. Sean Crosson. Jonathan will continue studying signal transduction in the organism Brucella abortus.