CAREER: Dissecting the Molecular Determinants of Specificity in Two-Component Signal Transduction Systems

Massachusetts Institute Of Technology, Cambridge MA

Investigators

Abstract

CAREER: Dissecting the Molecular Determinants of Specificity in Two-Component Signal Transduction Systems Two-component signal transduction systems, comprised of histidine kinases and their cognate response regulators, are one of the predominant means by which bacteria sense and respond to environmental stimuli. The versatility of these systems is reflected in their prevalence throughout the bacterial kingdom, with most species encoding tens or hundreds of such proteins. The faithful transmission of information through these signaling pathways and the avoidance of harmful cross-talk demand exquisite specificity of kinase-regulator interactions. This project aims to map the amino acids that dictate the specificity of these interactions. The work incorporates both computational studies of amino-acid coevolution as well as rational mutagenesis coupled with detailed biochemical characterizations. Finally, the research aims to examine the fitness consequences to increased cross-talk between closely-related pathways. This work will help to reveal (i) the fundamental basis of molecular recognition in an important class of signaling proteins and (ii) how cells coordinate the specificity of multiple, highly-related pathways. Broader Impacts: Understanding protein-protein specificity is a fundamental challenge in biology. While structural approaches can sometimes reveal the basis of specificity, that is not always the case, and some transient signaling complexes are refractory to structural analysis. The tools and approaches developed in this project may serve as an alternative, or complement, to structural approaches for understanding protein-protein interactions. Finally, a complete understanding of interaction specificity will enable the rational reprogramming of signaling pathways, leading the way to better, more sophisticated synthetic signaling circuits, with potential applications in bioremediation and biosensor development. This project also includes efforts by the primary investigator to develop and enhance two innovative new courses. As biology becomes an increasingly quantitative discipline, there is an urgent need to update the training of today's graduate students. The PI aims to further develop a new course called "Quantitative Biology" that provides graduate students at MIT with critical skills in statistics, probability, bioinformatics, microarray analysis, modeling, and systems biology. In addition to traditional lectures and primary literature discussions, students learn Matlab, a powerful tool for solving mathematical and computational problems in biology. The PI is also developing a new laboratory course that enables undergraduates to conduct novel, cutting-edge research projects using new tools and technologies, such as DNA microarrays. Finally, the PI is also actively involved in establishing a new, interdisciplinary microbiology graduate program.