The molecular determinants of surface-templated self-association of intrinsically disordered proteins

本质无序蛋白质表面模板自缔合的分子决定因素

• 批准号: 10715794
• 负责人: Peter J Chung
• 金额: $ 41.39万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10715794
• 关键词: Affinity; Behavior; Biological; Biological Models; Biophysics; Communities; Disease; Goals; Intention; Laboratories; Membrane; Methods; Microtubules; Modification; Molecular; Molecular Biology; Neurobiology; Neurodegenerative Disorders; Neurons; Organelles; Physical condensation; Physiological; Physiology; Predisposition; Protein Conformation; Proteins; Protocols documentation; Public Health; Recording of previous events; Research; Structure; Surface; Synaptic Vesicles; Techniques; alpha synuclein; insight; multidisciplinary; novel; programs; protein function; tau Proteins; tool

Project Summary The long-term goal of our research program is to utilize new techniques and paradigms to understand the molecular determinants of physiological and disease-relevant phenomena associated with intrinsically disordered proteins (IDPs), or proteins that do not fold into stable structures in solution. Our focus is the self- association of IDPs that occur on high-affinity surfaces (such as microtubules or organelle membranes). Surfaces can promote self-association by increasing the local IDP concentration and templating IDP conformations more susceptible to self-association. However, both IDPs and their respective high-affinity surfaces are subject to numerous cellular modifications, dramatically expanding the experimental parameter space necessary to precisely characterize this phenomenon. Understanding how self-association is controlled in this space could be central to understanding their function in physiology and disease. Thus, our laboratory will adapt novel tools beyond traditional molecular biology to recreate conditions in two model systems where this phenomenon occurs: Tau condensation on microtubules and α-synuclein multimerization on synaptic vesicle membranes. Not only does the PI have extensive expertise with biophysically characterizing these IDPs, but the importance of Tau and α-synuclein to neurobiology and neurodegenerative disease provide a rich history of experimental insights that can be applied towards this phenomenon. Combined, this expertise and background can be incorporated into the phenomenon of surface-templated self-association of these IDPs. Furthermore, we will establish protocols/methods that can be easily exported to study other IDPs that undergo surface-templated self- association, as well. Overall, our intention by precisely understanding phenomena associated with select IDPs is to create generalizable mechanisms by which other IDPs behave, eventually providing a rigorous framework that has explanatory and predictive power for these proteins. By undertaking the proposed research, we hope to transition our purely biophysics laboratory to an entirely multidisciplinary program that connects protein behavior to cellular phenomenon.

项目摘要 我们的C搜索计划的长期目标是利用新技术和范式来了解您 与本质上相关的生理和疾病现象的分子决定因素 蛋白质无序蛋白（IDP）或蛋白质不折叠成溶液中稳定结构的蛋白质。 在高亲和力表面上发生的IDP（例如微管或细胞器膜） 可以通过增加局部IDP的控制和模板IDP构象来促进自我关联 易于自我关联。 大量的细胞修饰，急剧扩展了实验参数空间 精确地表征了这种现象。 了解它们在生理和疾病中的功能。 除传统的分子生物学外，还可以在两个模型系统中重现条件 发生：微管上的Tau缩合和突触囊泡膜上的α-突触核蛋白多聚化 只有在表征这些IDP的生物物理学方面才有广泛的专业知识，但是 TAU和突触核素对神经生物学和神经退行性疾病提供了丰富的实验史 可以将其应用于当时的洞察力。 将这些IDP的表面自我关联的现象纳入了我们 建立可以容易导出的协议/方法，以研究其他经历表面自我的IDP 总体而言，我们的意图也是我们的意图 是要折磨其他IDP的可概括机制，最终提供严格的框架 这具有这些蛋白质的解释和预测能力。 过渡我们的生物物理学实验室到条目多阶级学会计划蛋白质行为 到细胞现象。