Principal Investigator Michael Laub
Another major focus in the lab is understanding how cells maintain the specificity of signaling systems. Given the highly related nature of the two-component signaling proteins in bacteria, how do cells maintain the insulation of different pathways? What prevents harmful cross-talk? How are signals integrated? We use both computational and experimental approaches to answer these questions.
We have found that histidine kinases exhibit a strong, system-wide kinetic preference in vitro for their in vivo substrate response regulators. This suggests that specificity in two-component signaling systems is intrinsic to the molecules and that additional factors, such as scaffolds, could enhance specificity but are not essential. To map the domains and amino acids which dictate kinase specificity we are examining the behavior of chimeric kinases and using a variety of mutagenesis techniques. In addition we have looked for amino acids in cognate pairs of histidine kinases and response regulators which co-evolve. Using the results of these studies we are attempting to “rewire” signaling pathways, both as a test of how well we understand specificity and potentially for the design of bacteria with novel signaling capabilities. Identifying the molecular basis of kinase specificty will also enable us to investigate the evolution of signal transduction systems and the selective forces which shape large, paralogous gene families.