The Molecular Basis of Cadherin-Mediated Cell Adhesion

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The main objective of this project is to understand the molecular basis of cadherin-mediated cell-cell adhesion. Cadherins are a family of molecules that are located on the surfaces of many cells. When like cells come in contact they adhere to one another whereas cells of different types tend to separate. This crucial property, which allows different tissues in the body to form and to separate from one another, can be traced to the molecular properties of individual cadherin molecules. But different cadherin family members are all similar to one another. What mechanisms allow small molecular differences to mediate highly specific cellular behavior? To address these questions, binding affinities of wild type and designed mutant cadherins will be carried out with the goal of modifying their behavior in controlled ways. The experimental work will be based on the use of theoretical methods that will elucidate the molecular basis of cadherin binding. The second stage of the project will focus on relating molecular to cellular properties. Once cells containing cadherins begin to adhere, the cadherins on each cell tend to cluster together to form junctions. Simulations will be carried out to clarify how this occurs and, based on the results that are obtained, new theoretical methods to simulate cellular processes will be developed. This research project represents an integrated research effort involving both theory and experiment and spans quite diverse disciplines including molecular modeling and simulation, structural biology, solution biophysics, and cell biology.The project is multi-scale and interdisciplinary in nature and the strategy that is being developed can serve as a model for other such efforts that integrate computational methods in cutting edge areas of modern biology. A particularly important element of the project is the development of scientists with expertise in both computational and experimental work including joint mentoring from senior researchers with very different backgrounds. The training of women and minority scientists is an integral component of the research. The lab participates in the EXROP (Exceptional Research Opportunities) program organized by HHMI and, in this context, hosts minority undergraduate students each summer. Both undergraduate and graduate minority students trained in the lab have become highly successful research scientists.This project is jointly supported by the Biomolecular Systems and Cellular Systems Clusters in the Division of Molecular and Cellular Biosciences.