The long term goal of this project is to characterize the role of desmocollins in cell-cell adhesion. Desmocollins are major glycoprotein components of the desmosome, and the targets of adhesion-disrupting antibodies present in the sera of patients with the severe blistering disease pemphigus vulgaris. Structurally, they form a distinct subset of the cadherins, a family of cell-cell adhesion and recognition molecules. Desmocollins occur as a number of tissue-specific isoforms generated by alternative splicing. The precise roles of these isoforms are not known. It is hypothesized that they are essential to the adhesive mechanism of the desmosome and may play a role in cellular recognition, cytoskeletal binding and the reception and transduction of initial cell-cell contact signals. The distribution of the desmocollin isoforms in both adult tissues and during embryonic development will be examined immunochemically and by PCR techniques to determine whether the pattern of expression is compatible with a role in morphogenesis. The interactions of the isoforms with other junctional components and with kinases will be examined, by co-precipitation and in vitro binding assays, to identify whether they function in signal transduction and/or cytoskeletal binding. Similar techniques will be used to define whether their association in the plane of the membrane is homotypic or heterotypic. The sequences that mediate and regulate the binding affinity of these molecules will be studied by comparing the capacity of wild type and recombinant desmocollins to support cell-cell adhesion and the ability of adhesion disrupting antibodies to interfere with this process. The sequences that govern the specific targeting of desmocollins and cadherins to their neighboring but biochemically distinct membrane domains will be studied by examining the junctional localization of chimeras of these molecules. These studies should provide new insights into the specific role of the desmocollins in cell-cell adhesion as well as the pathogenesis of the blistering disease pemphigus vulgaris.
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