Transitions to Excellence: Structural Cell Biology of Kinesin Motor Proteins

向卓越过渡：驱动蛋白运动蛋白的结构细胞生物学

• 批准号: 2128166
• 负责人: Claire Walczak
• 金额: $ 74.83万
• 依托单位: Indiana University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2128166&HistoricalAwards=false
• 关键词: Transitions; Excellence; Structural; Cell; Biology

Nearly all cells in our bodies contain miniaturized cellular highways, known as the microtubule cytoskeleton, that are used as tracks for transport of material inside cells. These structures also help drive cell movement and form the machinery necessary to segregate the genetic material during cell division. Unlike the rigid cement foundation of a roadway, cellular highways are unique in that they are rigid enough to support movement of material that is a hundred times its size, and yet they are dynamic and can be reorganized in a matter of seconds. This project addresses how cellular motors both move on the cellular highways and control their reorganization, which will provide fundamental new insights into cytoskeletal regulation in cells. This project will also have broader impacts through training and mentoring of both undergraduate students and high-school students, including URM students from multiple IU sponsored programs. The study of molecular motor proteins provides an ideal learning tool for students to literally “see” science in action at the molecular scale in addition to learning about the scientific process of data collection, analysis and presentation. In addition, this project will develop a new career mentoring program for undergraduate students in two IU sponsored research programs to help students navigate career choices at an earlier stage of college and broaden their participation in STEM careers.Molecular motor proteins that walk along the microtubules are part of families of enzymes, called kinesins, that share a conserved catalytic domain used to walk along the microtubule and a non-catalytic tail domain that determines specificity of their action in cells. This project seeks to elucidate the mechanisms that control the regulation of tail binding specificity. While cell biological approaches can uncover where a motor acts, and biochemical approaches can indicate which proteins it binds to and how tightly, a detailed molecular understanding can best be achieved through structural studies that will elucidate how different motor and tail domains are organized along the microtubule lattice. Structural understanding of the microtubule has been transformed by recent advances in the field of cryo-electron microscopy. The project will utilize cryo-electron microscopy to address how motor and non-motor tail domains of a single kinesin motor interact with the microtubule and will test how a conserved regulator modulates binding of multiple motor tail domains. In addition, this project will provide collaborative training in cryo-electron microscopy for a senior level cell biologist to expand their research program through the implementation of this powerful technology. These studies will provide new insights into understanding how microtubule structure impacts both dynamics and transport properties of molecular motors.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.

我们体内的几乎所有细胞都包含微型的细胞高速公路，称为微管细胞骨架，它们被用作材料内部材料内部的轨道。这些结构还有助于驱动细胞运动并形成在细胞分裂过程中隔离遗传物质所需的机械。与道路的刚性水泥基础不同，蜂窝高速公路的独特之处在于它们足以支撑其大小的一百倍的材料运动，但它们是动态的，并且可以在几秒钟内进行重新组织。该项目介绍了细胞电机如何在细胞高速公路上移动并控制其重组，这将为细胞中细胞骨架调节提供基本的新见解。该项目还将通过对本科生和高中生（包括来自多个IU赞助计划的URM学生）的培训和心理来产生更大的影响。分子运动蛋白的研究为学生提供了理想的学习工具，除了学习数据收集，分析和呈现的科学过程外，还可以在分子尺度上“参见”科学。此外，该项目将在两个IU赞助的研究计划中制定一项新的职业心理计划，以帮助学生在大学阶段的早期阶段进行职业选择，并扩大他们参与STEM职业的参与。沿着微蛋白行走的各种分子运动蛋白。沿着微蛋白行走，是酶的一部分，是酶促的动力素的一部分，该蛋白质与无限制的型号的动力不良，该蛋白质与无限型邻近的凝聚型型号，该蛋白质是养成的，该蛋白质是养成型的，该蛋白质是养成型邻域的，该蛋白质是依赖型号的，该蛋白质是依赖型号的，该蛋白质是依赖型号的，该蛋白质是依赖型号的，该蛋白质是依赖型号的型号。它们在细胞中的作用的特异性。尽管细胞生物学方法可以揭示运动的作用，并且生化方法可以表明它与哪种蛋白结合，以及如何通过结构研究最好地实现详细的分子理解，从而阐明如何阐明如何沿着微管晶状体组织不同的运动和尾部结构域。微管对微管的结构理解已通过冷冻电子显微镜领域的最新进展进行了转化。该项目将利用冷冻电子显微镜来解决单个驱动蛋白电动机的电动机和非运动尾部结构域与微管相互作用，并将测试保守的调节器如何调节多个电动机尾域的结合。此外，该项目将在冷冻电子显微镜中提供合作培训，以使高级细胞生物学家通过实施这项强大的技术扩大其研究计划。这些研究将提供新的见解，以了解微管结构如何影响分子电机的动态和运输特性。该奖项反映了NSF的法定任务，并且使用基金会的知识分子和更广泛的影响审查标准，被认为值得通过评估来支持。