Molecular Mechanisms of Cell-Cell Attachment

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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.