Specific protein-protein interactions are required for virtually all cellular functions. Nonetheless, the molecular basis for specificity in these interactions remains incompletely understood. The proposed research will explore factors leading to specificity in coiled-coil interactions. Coiled coils provide a useful model system for the study of specific interactions among proteins and for the development of new biochemical methods for characterizing these interactions. In addition, as coiled-coil domains are found in a wide variety of proteins of biological and medicinal interest, the detailed study of this class of proteins has implications for our understanding of phenomena ranging from transcription to cytoskeletal structure and function. We propose a method for using sequence-specific DNA binding as a probe for helix orientation preference and for partner specificity in coiled coils. This strategy allows us to generate and quantitatively test large numbers of mutant coiled coils efficiently. It also permits us to take advantage of in vivo selection techniques. Specifically, we describe an approach for selecting antiparallel coiled coils from randomized protein libraries. No other method is currently available for distinguishing between parallel and antiparallel coiled coils in vivo. The rules we identify for helix orientation preference and partner specificity will lead to an improved understanding of protein molecular recognition and facilitate the design of coiled-coil proteins with improved or novel recognition properties. In addition, these studies will also be crucial for translating the primary sequence of putative coiled-coil proteins into structural and functional information.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Bio-Organic and Natural Products Chemistry Study Section (BNP)
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Li, Jerry
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Indiana University Bloomington
Schools of Arts and Sciences
United States
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Waldman, Vincent M; Stanage, Tyler H; Mims, Alexandra et al. (2015) Structural mapping of the coiled-coil domain of a bacterial condensin and comparative analyses across all domains of life suggest conserved features of SMC proteins. Proteins 83:1027-45
Weitzel, Christopher S; Waldman, Vincent M; Graham, Travis A et al. (2011) A repeated coiled-coil interruption in the Escherichia coli condensin MukB. J Mol Biol 414:578-95
Li, Yinyin; Schoeffler, Allyn J; Berger, James M et al. (2010) The crystal structure of the hinge domain of the Escherichia coli structural maintenance of chromosomes protein MukB. J Mol Biol 395:11-9
Li, Yinyin; Stewart, Nichole K; Berger, Anthony J et al. (2010) Escherichia coli condensin MukB stimulates topoisomerase IV activity by a direct physical interaction. Proc Natl Acad Sci U S A 107:18832-7
Li, Yinyin; Weitzel, Christopher S; Arnold, Randy J et al. (2009) Identification of interacting regions within the coiled coil of the Escherichia coli structural maintenance of chromosomes protein MukB. J Mol Biol 391:57-73
McClain, D L; Binfet, J P; Oakley, M G (2001) Evaluation of the energetic contribution of interhelical Coulombic interactions for coiled coil helix orientation specificity. J Mol Biol 313:371-83