The cell surface mediates the flow of information and metabolites between a cell and its environment. The model of cell surface membranes is evolving from one that emphasizes mobility and autonomy of membrane constituent molecules, to another that emphasizes the lateral concentration of membrane proteins and lipids into patches that are often interpreted as showing that these molecules are confined in membrane domains. While a variety of experiments report the existence of membrane domains, the mechanisms of patch formation, and by implication, the mechanisms of domain creation are largely unknown. Specific interactions between molecules are involved in the formation of very small patches of proteins or lipid but the mechanisms that create large membrane domains, 100s of nm in diameter, are unknown. Without understanding these mechanisms one cannot understand the importance or relevance of membrane domains for cell surface membrane function in normal and abnormal cells. The PI has developed a model, a numerical simulation model based on experimental data, for large-scale domain formation in cell plasma membranes. The model assumes no specific interactions between membrane proteins and lipids. Rather, it depends upon the lateral diffusion coefficients of membrane proteins and lipids, upon the occurrence and stability of barriers to lateral mobility, and upon vesicle traffic to and from the surface. The PI finds that both vesicle traffic, and dynamic barriers to lateral mobility are required to create and maintain lateral heterogeneities in membranes consistent with domains 100s of nm in diameter. In the absence of either barriers to lateral mobility or vesicle traffic, lateral diffusion randomizes the distribution of membrane molecules. The model implies that the apparent concentration of proteins and lipids in membrane domains may be a nonspecific consequence of membrane physics and cell metabolism. The PI proposes to test his model using cells in which the barriers to lateral mobility are defective, sph/sph, alpha-spectrin-deficient, erythroleukemia cells, and cells in which vesicle traffic from and to the surface is inhibited.
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