Core B: Macromolecular and Cellular Structure Core

项目总结 大分子和细胞结构核心的主要目标是提供尖端技术， 为响应U54 FTD中心的需求和发现而进行结构表征的创新平台 没有围墙。这个没有围墙的FTD中心的长期目标是了解 Tau是如何被伴侣和辅伴侣稳定的，以及它是如何被 溶酶体。该核心将使用CryoEM中的最新方法来确定原子分辨率 项目1、2中定义的相关蛋白质和蛋白质复合体的结构，并提供细胞 通过低温电子显微镜断层扫描研究tau溶酶体降解的背景。高分辨率研究将通过以下方式实现 关键蛋白质-蛋白质复合体的表达、体外重组及新型低温电子显微镜网格 阿加德实验室开发的技术。此外，核心将利用其生化专业知识来量化 通过RTQuiC检测该中心其他部分是否存在tau种子。总而言之，贡献 这一核心将具有重要意义，因为它们将揭示决定tau周转的基本机制，并提供 潜在治疗干预的新靶点。

PROJECT SUMMARY The primary objective of the Macromolecular and Cellular Structure Core is to provide cutting edge, innovative platforms for structural characterization responsive to needs and discoveries of the U54 FTD Center without Walls. The long-term goal of this FTD Center without Walls is to understand the overall metabolism of tau, how it is stabilized by chaperones and cochaperones and how it is channeled for degradation by the lysosome. This core will use the latest methodologies in cryoEM to determine atomic resolution cryoEM structures of relevant proteins and protein complexes as defined in Projects 1, 2 and to provide a cellular context for tau lysosomal degradation via cryoEM-Tomography. The high-resolution studies will be enabled via the expression and in vitro reconstitution of critical protein-protein complexes and novel cryoEM grid technologies developed by the Agard lab. Additionally, the core will use its biochemical expertise to quantify the existence of tau seeds for the other parts of the Center via RTQuiC assays. Together, the contributions from this Core will be significant as they will reveal fundamental mechanisms dictating tau turnover and provide novel targets for potential therapeutic intervention.