A large number of proteins are involved in regulating the process of transcribing genes. These proteins participate in distinct protein-protein and protein-DNA interactions. The union of a series of protein-protein and protein-DNA interactions governs the overall fidelity and efficiency of the transcriptional process. The conventional view is that the specificity of these interactions requires that the relevant proteins adopt well-defined three-dimensional structures in order to recognize their cognate protein / DNA interaction partners. This view has been challenged by the observation that a majority of the proteins involved in transcriptional regulation fail to adopt well ordered structures in their unbound forms. These so-called intrinsically disordered proteins or IDPs play central roles in the overall process of transcribing genes. How IDPs manage to function without prior folding remains a mystery. This project will attempt to make progress on this matter through quantitative studies that blend computer simulations, polymer physics, spectroscopic measurements, and functional assays. Progress will be achieved through coordinated studies on three sets of distinct IDPs that are involved in different steps of the transcriptional process. The studies will yield a quantitative framework for describing the conformational ensembles IDPs, which in turn will facilitate the deciphering novel mechanisms for molecular recognition based on disordered as opposed to pre-folded proteins. These mechanisms will have implications for understanding the responses of networks of protein-protein and protein-DNA interactions to cues that lead to cellular level decisions such as cell division, cell differentiation, and cell death.
The investigator's efforts in three synergistic areas will broaden the impact of the project's research. 1) Graduate students and other trainees in the investigator's lab have been involved in the Young Scientist Program (YSP) http://ysp.wustl.edu at Washington University (WU). This program attracts high school students from disadvantaged backgrounds into scientific careers through activities that emphasize research and interactions between high schoolers and trainees at WU. The YSP also recruits St. Louis inner city public high school teachers to work with researchers in order to facilitate inquiry-based learning in the classroom. Trainees from the investigator's lab will continue to participate in the YSP. Additionally, St. Louis inner city public school teachers will be recruited to spend some fraction of their summers working in the PI's lab supported by funds from the YSP. If successful, this will enable the translation of findings from the proposed research into teaching modules that can be incorporated into high school science curricula. 2) The investigator is actively involved in the McKelvey Scholars program at WU that supports the research activities of undergraduates majoring in science and engineering. Women make up more than 60% of this cohort and the necessary network has been set up to bring these undergraduates to be actively involved in the project. 3) The investigator is actively involved in outreach and public relations efforts for the IDP subgroup within the Biophysical Society and these activities will continue over the project period.