The composition and function of the plasma membrane is maintained by a complex intracellular traffic moving cell surface glycoproteins between organelles. This requires the recognition and sorting of different classes of proteins, not only during biosynthesis, but also during redistributive processes, such as the internalization and recycling of receptors during receptor-mediated endocytosis, transcytosis, or during the down-regulation of hormone receptors. Disease can result from the failure of any one of these processes, or from its subversion for use by a pathogen such as a virus. The focus of the work described in this application is to determine the molecular details of post-Golgi sorting events. By establishing the details of sorting events for a few, well- understood proteins such as the influenza virus hemagglutinin and polyimmunoglobulin receptor, we intend to provide the basis for a comparison of the sorting events that occur in other cell types involving other proteins. Once the relationship between the sorting of different proteins in different cell types is understood, it may be possible to use this information for diagnostic purposes. Studies in vitro of cell types easily isolated from human patients might be used to learn about disease processes in organs for which biopsy material is limiting, difficult to isolate, or the cells difficult to maintain in culture. Experiments proposed in this application will test the hypothesis that transmembrane proteins contain hierarchies of sorting signals that allow them to be transported and localized to different destinations in different cell types. We will investigate potential apical sorting information in the transmembrane segments of a number of proteins for the purpose of establishing a consensus sequence for this type of sorting signal. We propose to identify proteins that bind to sorting signals and to determine the role of glycosphingolipid-enriched membranes in the sorting of the influenza virus hemagglutinin and other proteins sorted to the apical surface of epithelial cells or axons of neurons.
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