Fidelity and Regulation of Signal Recognition Particle

了解新合成蛋白质的细胞“邮件分配”系统对于理解生命本身以及利用和改造生物体来解决诸如食物和清洁能源等社会需求具有重要意义。除了对社会需求的基本理解和支持外，该项目还将为科学教育和应对2019冠状病毒病大流行带来的相关挑战提供极好的机会。研究结果将通过学术期刊的出版物和在科学会议上的报告以及与一般公众直接接触的演讲论坛来传播。该项目的教育部分将强调培养多学科生物化学和生物物理研究方面的研究生和博士后学者。它还将使高中生和本科生接触到最先进的研究工具，并为研究生和博士后提供领导经验。最后，该项目将产生对许多其他研究人员有用的有价值的试剂、工具和分析方法。真核细胞是高度区隔的，每个细胞器都含有一组独特的蛋白质，这些蛋白质赋予了细胞器的结构和功能。为了维持细胞的高阶结构和正常功能，所有新合成的蛋白质都需要定位到正确的细胞目的地。为了实现这一目标，细胞进化出了一种普遍保守的蛋白质靶向机器——信号识别粒子（SRP），以识别并将新合成的蛋白质传递到合适的细胞膜。本项目旨在了解SRP在细胞中如何被调控以确保蛋白定位的细胞器特异性，以及SRP与SRP受体和新生蛋白的复合物如何在靶膜上被分解以使新生蛋白有效插入。拟议的项目将结合Shan实验室在机械生物化学方面的专业知识和Weiss实验室在生物物理学方面的专业知识来破译SRP复杂的时空调节。结果将揭示确保细胞中“邮件传递”系统正常运作的一般原则。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Understanding the cellular ‘mail distribution’ system of newly synthesized proteins is of fundamental importance for understanding life itself and for harnessing and engineering organisms to solve societal needs such as food and clean energy. In addition to the basic understanding and support for societal needs, this project will provide excellent opportunities for science education and the associated challenges that emerged from the COVID-19 pandemic. The results of the research will be disseminated through publications in academic journals and presentations at scientific conferences, as well as lecture forums that directly interface with the general public. The education component of the project will emphasize the training of graduate students and postdoctoral scholars in multidisciplinary biochemical and biophysical research. It will also expose high school and undergraduate students to state-of-the-art research tools and provide leadership experience for the graduate students and postdocs. Finally, the project will generate valuable reagents, tools, and assays that are useful to many other researchers.Eukaryotic cells are highly compartmentalized, with each organelle harboring a unique set of proteins that endow the organelle its structure and functions. To maintain the higher order structure and proper functioning of the cell, all newly synthesized proteins need to localize to their correct cellular destinations. To accomplish this, cells have evolved a universally conserved protein targeting machine, signal recognition particle (SRP), to recognize and deliver newly synthesized proteins to the appropriate cellular membrane. This project aims to understand how SRP is regulated in the cell to ensure the organelle specificity of protein localization, and how its complex with the SRP receptor and the nascent protein is disassembled at the target membrane to allow efficient insertion of nascent proteins. The proposed project will combine the expertise of the Shan lab in mechanistic biochemistry and the Weiss lab in biophysics to decipher the sophisticated spatiotemporal regulation of SRP. The results will reveal generalization principles that ensure the proper functioning of the “mail delivery” system in the cell.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.