Evolutionary Genomics of Methyl-accepting Chemotaxis Proteins
Alexander, Roger Parker
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The general goal of this project was to use computational biology to understand signal transduction mechanisms in prokaryotes. Its specific focus was to characterize the cytoplasmic domain of methyl-accepting chemotaxis proteins (MCP_CD), a protein domain central to the function of chemotaxis, the most complex signaling network in prokaryotes. Chemotaxis enables cells to sense and respond to multiple external and internal stimuli by actively navigating to an optimal environment. MCP_CD is a central part of this circuit, but its coiled coil structure is difficult to analyze using traditional tools of computational biology. In this project, a new method for analysis of the domain was developed and used to gain insight into its function and evolution. Research advance 1: Characterization of the MCP_CD protein domain. Before this work, MCP_CD was known to have two distinct functional regions: the signaling region that activates the histidine kinase CheA and the methylation region where adaptation enzymes CheB and CheR store information about recent stimuli. The result of this project is classification of ~2000 MCP_CDs into twelve subfamilies. The unique mechanism of evolution of the domain has been clarified and precise boundaries of the adaptation and signaling regions determined. A new functional region, the flexible bundle subdomain, was identified and its contribution to the signaling mechanism elucidated by analysis of conserved sequence features. Conserved and variable sequence features in the adaptation and signaling subdomains led to a better understanding of the evolutionary history of the adaptation mechanism and of alternative higher-order arrangements of receptors within the membrane. Research advance 2: Development of a sensor / kinase correlation algorithm to couple diverse MCP_CD and kinase subfamilies. The receptor diversity discovered in this work is complemented by diversity in the kinases with which they interact. In this work, an algorithm was developed to associate receptor / kinase pairs which facilitated understanding of the function and evolution of chemotaxis. Research advance 3: Development of Cheops, a database of chemotaxis pathways. The Cheops (Chemotaxis operons) database presents the results of the sensor / kinase correlation algorithm and the information about receptor and kinase diversity in an integrated and intuitive way.