CAREER: Molecular heterogeneity and the regulation of cell adhesion by force

Case Western Reserve University, Cleveland OH

Investigators

Abstract

CAREER: Molecular heterogeneity and the regulation of cell adhesion by force All close contacts between cells inside the human body involve specialized molecules known as adhesion proteins. These molecules participate in transmitting signals, for example recruiting immune cells to the sites of inflammation, and are critical to the development and maintenance of tissues. The mechanical forces that these proteins feel when they bind to their targets can dramatically alter their behavior, controlling how long the bond endures before breaking. In many cases this regulation is counterintuitive, with larger tension leading to longer bond lifetimes, and the underlying microscopic mechanisms are poorly understood. This project aims to investigate those mechanisms through theory and computations, creating general methods for analyzing experimental data that will elucidate the molecular details of adhesion in a variety of biological contexts. The focus will be on protein heterogeneity-the diverse structural states which adhesion bonds can assume, each with its own characteristic response to applied forces. The project will integrate cutting-edge biophysics research into undergraduate education through the BIOREPS (BIOphysical REsearch Problem Set) initiative. Students in an undergraduate biophysics course will transform recent high-profile research articles into problem sets published in an open online database. These activities will give students valuable experience in scientific pedagogy and communication. The resulting database will become a unique resource, available to all educators looking for research-based course materials. This project's research strategy is based on the following hypothesis: the regulation of adhesion protein bonds by tension can be explained by characterizing their heterogeneous conformational states, and resolving how the protein switches between states under various force conditions. This project will identify and describe the multiple conformational states of the bonds directly from data gathered by single-molecule force spectroscopy experiments. This project will develop new theoretical approaches that bridge the divide between experimental measurements and the microscopic mechanisms of adhesion to overcome the challenge of deciphering the molecular details from the data. This project will also develop structure-based models that relate observable bond dynamics in specific systems to tension-induced changes in protein configuration and bond energies. Parallel focus on data analysis and model development provides a comprehensive framework for discovery, drawing on the mutual feedback between experiment and theory. The research will provide direct insights into adhesion, but also aid the development of new and more informative experimental protocols.