Phase Behavior of Intrinsically Disordered Proteins

本质无序蛋白质的相行为

• 批准号: 1121867
• 负责人: Rohit Pappu
• 金额: $ 84.71万
• 依托单位: Washington University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1121867&HistoricalAwards=false
• 关键词: Phase; Behavior; Intrinsically; Disordered; Proteins

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.

大量蛋白质参与调节基因转录过程。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明确定义的三维结构，以识别其同源蛋白质/ DNA相互作用伴侣。这一观点受到了以下观察结果的挑战，即大多数参与转录调控的蛋白质在其未结合形式下不能采用良好有序的结构。这些所谓的内在无序蛋白质或IDP在基因转录的整个过程中发挥着核心作用。国内流离失所者如何在没有事先折叠的情况下发挥作用仍然是一个谜。该项目将试图通过计算机模拟、聚合物物理学、光谱测量和功能分析相结合的定量研究在这一问题上取得进展。将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，取得进展。这些研究将产生一个定量的框架来描述构象集合IDP，这反过来又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。这些机制将对理解蛋白质-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）的线索的反应产生影响。 调查员在三个协同领域的努力将扩大该项目研究的影响。1)研究人员实验室的研究生和其他受训人员参与了华盛顿大学（WU）的青年科学家计划（YSP）。http://ysp.wustl.edu该计划吸引来自弱势背景的高中生进入科学事业，通过强调研究和高中生和学员之间的互动活动在吴。YSP还招募圣路易斯市中心公立高中教师与研究人员合作，以促进课堂上的探究式学习。来自研究者实验室的受训人员将继续参加YSP。此外，圣路易斯市中心的公立学校教师将被招募，在YSP的资金支持下，在PI的实验室工作一段时间。如果成功的话，这将使拟议研究的结果能够转化为可以纳入高中科学课程的教学模块。2)研究者积极参与了WU的McKelvey学者计划，该计划支持科学和工程专业的本科生的研究活动。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)调查员积极参与生物物理学会内国内流离失所者分组的外联和公共关系工作，这些活动将在项目期间继续进行。