Intellectual merit: Cadherins are proteins that protrude from the surface of cells and interact with identical proteins on neighboring cells to form adhesions between cells. These protein-protein interactions between cadherins on opposing cells lead to solid tissue formation. Such interactions are critical during normal processes such as development and tissue maintenance, and also during abnormal processes such a cancer. Neural-cadherins are found primarily in brain tissue. Epithelial cadherins are found primarily in epithelial cells. These two proteins are very close relatives, but must have some difference that makes them suited for their particular tissue type. The goal of this project is to investigate the differences in the protein-protein interactions in neural- and epithelial-cadherins that lead to their segregation into particular tissues. Recently, this laboratory has observed a very striking difference between these two proteins. Preliminary results indicate that the protein-protein interaction between neural-cadherins is very slow to dissociate while that between epithelial-cadherins dissociates quickly. This difference in assembly dynamics is so striking that it may explain the segregation of these two proteins into distinct physiological niches. Experiments proposed here elaborate this basic observation by studying the details of how the interactions occur and the factors that contribute to the difference in the dynamics of the interactions. The project will investigate the protein-protein interactions in solution and in single-molecule studies using fluorescence techniques.
Broader impacts. The experiments proposed here require the collaborative efforts and the diverse skills of the Pedigo and Hammer laboratories. The laboratories will use a wide range of experimental approaches that will expose students to diverse disciplines in chemistry. Training undergraduate and graduate students is critical to the research efforts of this project. The project will involve three graduate students as the core of the research team and a number of undergraduates through the Honors College and summer research internship programs at this university. The plan is to continue involvement in local and regional science education through visits of groups to the university, visits of students and faculty to elementary schools and participation in the science fairs.
Classical cadherins are cell adhesion proteins that important for adhering cells together in solid tissues in your body. The classical cadherin family of proteins has several members that are named for the tissue type in which they predominate. The two family members that we study are neural- (N-) and epithelial (E-) cadherins. We are interested in these two proteins because they are expressed in the brain at two different cell contacts. The specific localization of these proteins implies that they have characteristics that suit them to their specific location, or conversely that the properties of the cell contact is dictated by the characteristics of the protein that comprise it. From previous work, we knew that the time frame of the interactions between cadherin molecules for E and N- cadherins is radically different. The work that we accomplished over the funding period directly addressed the molecular origin of the differences between the time frames of interactions. This question is intrinsically interesting not only as a protein folding-function question, but also as a means to understand adhesion by classical cadherins, a phenomenon that is basic to solid tissue formation and maintenance in creatures from vertebrates to fruit flies. The broader impacts of our work are related to training of a young scientists including high school students (2), undergraduate students (20), graduate students (3) and a postdoctoral scientist (1). In the 4 years over which this project was funded we published 6 peer-reviewed publications with two additional manuscripts in revision. Ten of the students were women, four were African American and one was Hispanic.
