REPRESSOR AND ANTIREPRESSOR PROTEINS OF BACTERIOPHAGE

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The objective of this research program is to understand how sequence and structure determine specificity in assembly processes involving protein- DNA and protein-protein interactions. DNA-binding proteins are critical participants in many cellular and viral processes and their biological activities are frequently regulated by the binding of other proteins, by covalent modification, and/or by degradation. In each of these cases, specificity is critical. DNA-binding proteins must be capable of recognizing the correct sites in the presence of a vast excess of nonspecific DNA and regulatory modifications or binding events must be targeted to one or a few key proteins the cell. Understanding these processes is a key goal of basic research in molecular and structural biology, with potential applications in medicine, biotechnology, and the design of novel proteins and regulatory circuits. One of the long-term aims of our research program is to understand how the Arc repressor of phage P22, a ribbon-helix-helix transcription factor, binds operator DNA and regulates transcription. Other aims are to understand substrate recognition by the Tsp and Clp families of bacterial C-terminal specific proteases and to determine the mechanism and rules of the ssrA tagging system which mediates cotranslational addition of C-terminal peptides to proteins. In each of these systems, we week to understand how sequence and structural factors determine binding specificity. How does a transcription factor discriminate between operator and non-operator DNA? How do intracellular proteases select target substrates? What determines which intracellular proteins are cotranslationally tagged by the ssrA system? Transcription factors, proteolysis, and peptide tagging are also connected biologically; DNA-binding proteins are often the targets of C-terminal specific proteases and the ssrA system marks proteins for degradation by these enzymes.