Conformational Switch, Activation and Clustering in Cell Focal Adhesions

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Cells attach to a solid surface or to the tissue they are part of by connections called "focal adhesions". The cells interact mechanically and biochemically with their environment through the adhesions. This creates a mechanochemical coupling between the cells and their tissue. The coupling controls many biological functions of the cell, such as survival, change of the cell into another type and also whether it can move from one part of the body to another. The focal adhesions are part of the membrane that surrounds the cells of mammals, birds and reptiles. Since so many different species (including humans) have focal adhesions, understanding how they transmit mechanochemical signals will have broad applicability to understanding important biology. The research will create computer models of how the focal adhesion forms from the many molecules that are part of it and how the molecules interact to transmit signals. The computer models will be tested against real data collected as part of the research to ensure that they are correct. Understanding the formation and function of focal adhesions will ultimately inspire new types of cell-based medicine. This project requires several different fields of science including biology, chemistry, mechanics, and bioengineering. The principal investigator also will reach out to undergraduate students in these broadly spread disciplines by creating an annual workshop that includes underrepresented community college students to help broaden participation in engineering research.Understanding the detailed pathways for integrin activation, clustering, and recruitment and maturation of focal adhesions will provide insight on the regulatory mechanisms of cell-matrix signaling. While it is widely established that integrin signaling is dependent upon allosteric conformational changes that initiate at certain points in the molecule and propagate over the entire structure, the sequence of events leading to its activation and extensive conformational changes remains elusive in many aspects. The dynamic nature of the focal adhesion machinery and integrin conformational switch has so far hindered a full appreciation of the key events involved in the cell-matrix adhesion. With the advent of computational resources and advanced techniques, computational modeling can now be employed effectively to reconcile apparently contradictory experimental observations. This research is aimed at filling the knowledge gap on the mechanisms of focal adhesion formation. The research team will develop coarse-grained and molecular dynamics models to understand the mechanism of integrin activation, conformational switch and signal transduction. Using computational models and in vitro experiments, the competitive and cooperative roles of different focal adhesion proteins will be investigated.