The goal of this project is to understand protein evolution at the molecular level. An interdisciplinary approach will be taken that combines the strengths of evolutionary biology and molecular biophysics. As proteins evolve, they must maintain function or they will be removed by selection. Recent investigations using ancestral protein resurrection have found functional intermediates in the evolution of the medically important steroid receptor (SR) proteins. The mutational pathway connecting different functional states is characterized by strong sign epistasis: """"""""permissive"""""""" mutations must precede """"""""function-switching"""""""" mutations to maintain function along the evolutionary trajectory. The mechanism of these permissive mutations is not well understood. This project will use the methods of biophysics and directed evolution to determine the mechanisms of these historical permissive mutations.
The first aim of the project is to probe the relationship between protein stability and evolution.
The second aim i s to understand the role of contingency in the evolution of complex protein function. This work has important implications for understanding the general principles of protein evolution. It will also provide insight into the molecular determinants of ligand specificity in SRs, which will inform attempts to create novel therapeutic agents that modulate SR function.

Public Health Relevance

Steroid receptors-which are key players in diseases ranging from asthma to cancer-must discriminate between similar hormones to function properly. Like all proteins, their ability to perform this function is a product of their evolutionary history. This project attempts to understand how this function evolved, which will potentially allow for new drugs to modulate steroid receptor function to treat disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F04B-B (20))
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Flicker, Paula F
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University of Oregon
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Hart, Kathryn M; Harms, Michael J; Schmidt, Bryan H et al. (2014) Thermodynamic system drift in protein evolution. PLoS Biol 12:e1001994
Harms, Michael J; Eick, Geeta N; Goswami, Devrishi et al. (2013) Biophysical mechanisms for large-effect mutations in the evolution of steroid hormone receptors. Proc Natl Acad Sci U S A 110:11475-80
Harms, Michael J; Thornton, Joseph W (2013) Evolutionary biochemistry: revealing the historical and physical causes of protein properties. Nat Rev Genet 14:559-71
Williams, Sandra G; Harms, Michael J; Hall, Kathleen B (2013) Resurrection of an Urbilaterian U1A/U2Býýý/SNF protein. J Mol Biol 425:3846-62
Eick, Geeta N; Colucci, Jennifer K; Harms, Michael J et al. (2012) Evolution of minimal specificity and promiscuity in steroid hormone receptors. PLoS Genet 8:e1003072
Bridgham, Jamie T; Eick, Geeta N; Larroux, Claire et al. (2010) Protein evolution by molecular tinkering: diversification of the nuclear receptor superfamily from a ligand-dependent ancestor. PLoS Biol 8:
Harms, Michael J; Thornton, Joseph W (2010) Analyzing protein structure and function using ancestral gene reconstruction. Curr Opin Struct Biol 20:360-6