Molecular Mechanisms of Cell-Cell Attachment

细胞与其环境之间的粘附相互作用对细胞生命的几乎所有方面都至关重要。它们直接调节细胞组装成组织和器官，控制细胞运动，影响细胞形状，并协调决定细胞行为和命运的各种跨膜信号网络的激活。细胞迁移和细胞-细胞粘附之间的平衡是至关重要的，特别是当细胞在发育过程中迁移到特定部位时。在彼此接触时，细胞变得静止并分化成组织，对于所述组织，强的细胞-细胞粘附是维持组织完整性所必需的。另一方面，细胞-细胞粘附的变化重新启动细胞迁移以允许例如伤口愈合所必需的细胞更新。该项目旨在通过研究关键调节因子α-连环蛋白来促进我们对细胞间粘附的理解，α-连环蛋白是细胞间连接力的关键传感器。这项工作将提供结构的见解，以进一步我们的不同的α-连环蛋白功能状态的机械理解。 此外，该项目还包括一个面向代表性不足的少数民族，特别是年轻人口的教育外展部分，包括为7年级和8年级学生举办的实践讲习班：DNA提取讲习班和药物发现讲习班;研究人员参加由William R.小凯南慈善信托，其中导师高中学生在夏季六个星期，并提供实践研究经验;和研究生课程教师任命的PI。该研究项目将使用第一台300 kV低温原子分辨率显微镜（cryoARM 300）提供脂筏和非筏膜条件下α-连环蛋白的新近原子分辨率结构。 这项工作是阐明与肌动蛋白细胞骨架结合的各种α-连环蛋白状态的机制和特定功能的第一步。 生化和细胞分析将进一步验证结构发现。因此，细胞-细胞粘附的重要机制的见解将导致从这个项目。该项目由生物科学理事会分子和细胞生物科学部的分子生物物理学和细胞动力学与功能集群支持。该奖项反映了NSF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。

Adhesive interactions between cells and their environment are crucial for nearly all aspects of the life of cells. They directly regulate the assembly of cells into tissues and organs, control cell motility, affect cell shape, and orchestrate the activation of diverse transmembrane signaling networks which determine the behavior and fate of cells. The balance between cell migration and cell-cell adhesion is crucial in particular when cells migrate to specific sites during development. Upon contact with each other, cells become stationary and differentiate into tissues for which strong cell-cell adhesion is necessary to maintain tissue integrity. On the other hand, changes in cell-cell adhesion reinitiate cell migration to allow cell turnover necessary for example for wound healing. The project seeks to advance our understanding of cell-cell adhesion by studying the key regulator, alpha-catenin, that functions as a crucial sensor of force of cell-cell junctions. This work will provide structural insights to further our mechanistic understanding of the distinct alpha-catenin functional states. Additionally, this project includes an educational outreach component geared towards the underrepresented minorities and in particular the younger population, including an established hands-on workshops for 7th and 8th graders: a DNA extraction workshop and a drug discovery workshop; the researchers' participation in the High School Student Summer Internship Program funded by the William R. Kenan, Jr. Charitable Trust where the mentor high school students for six weeks in the Summer and provide hands-on research experience; and the Graduate Program faculty appointment of the PI. This research project will use the first 300 kV cryogenic Atomic Resolution Microscope (cryoARM300) to provide new near atomic resolution structures of alpha-catenin in lipid raft and non-raft membrane conditions. This work is a first step in elucidating the mechanism and specific functions of various alpha-catenin states that bind to the actin cytoskeleton. Biochemical and cellular assays will additionally validate the structural findings. Thus, significant mechanistic insights into cell-cell adhesion will result from this project. This project is supported by the Molecular Biophysics and Cellular Dynamics and Functions Clusters of the Division of Molecular and Cellular Biosciences in Biological Sciences Directorate.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.