Phase Behavior of Intrinsically Disordered Proteins

大量的蛋白质参与调控基因转录的过程。这些蛋白质参与不同的蛋白质-蛋白质和蛋白质- dna相互作用。一系列蛋白质-蛋白质和蛋白质- dna相互作用的结合决定了转录过程的整体保真度和效率。传统观点认为，这些相互作用的特异性要求相关蛋白质采用定义良好的三维结构，以便识别它们的同源蛋白质/ DNA相互作用伙伴。这一观点受到了一项观察的挑战，即大多数参与转录调节的蛋白质在其非结合形式下不能采用有序的结构。这些所谓的内在无序蛋白或IDPs在整个基因转录过程中起着核心作用。IDPs如何在没有事先折叠的情况下运作仍然是一个谜。该项目将尝试通过混合计算机模拟、聚合物物理、光谱测量和功能分析的定量研究在这一问题上取得进展。通过对参与转录过程不同步骤的三组不同的国内流离失所者进行协调研究，将取得进展。这些研究将产生描述构象集成IDPs的定量框架，这反过来将有助于破译基于无序而不是预折叠蛋白质的分子识别的新机制。这些机制将有助于理解蛋白质-蛋白质和蛋白质- dna相互作用网络对导致细胞水平决定（如细胞分裂、细胞分化和细胞死亡）的线索的反应。研究者在三个协同领域的努力将扩大项目研究的影响。1)研究员实验室的研究生和其他学员已参与华盛顿大学（WU）青年科学家计划（YSP） http://ysp.wustl.edu。该项目通过强调研究和高中生与WU学员之间的互动的活动，吸引来自弱势背景的高中生从事科学事业。YSP还招募圣路易斯内城公立高中教师与研究人员合作，促进课堂上的探究性学习。研究者实验室的受训者将继续参加YSP。此外，圣路易斯内城公立学校的教师将被招募到PI的实验室工作，并由YSP提供资金支持。如果成功，这将使拟议研究的结果能够转化为可纳入高中科学课程的教学模块。2)积极参与我校麦凯维学者项目（McKelvey Scholars program），该项目支持理工科本科生的研究活动。妇女占这一群体的60%以上，已经建立了必要的网络，使这些大学生积极参与该项目。3)研究者积极参与生物物理学会内部IDP小组的外展和公共关系工作，这些活动将在项目期间继续进行。

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.