Cellular responses to external signals begin at the plasma membrane, where the dynamic assembly of receptors can regulate cellular activity. Membrane-enveloped viruses, including the human immunodeficiency virus (HIV) also assemble at the plasma membrane, exploiting mechanisms evolved for cellular trafficking. However, our physical paradigm for how proteins form mesoscale assemblies is far from complete. While the organization and dynamics of membrane proteins are heterogeneous, commonly used fluorescence-based measurements lack information at the molecular scale. In contrast, single molecule measurements limited to looking at only a few molecules in a given cell lack ensemble information. Thus, the study of protein assembly has been limited by a lack of spatially resolved, dynamic information on ensembles of molecules. We will use super-resolution fluorescence imaging techniques combined with live cell imaging and single molecule tracking to determine how the dynamics of protein assembly are coordinated. The long-term goal of my research is to use quantitative fluorescence methods to identify the physical mechanisms for protein transport and organization in cells. The objective of this proposal is to establish quantitative models of protein assembly in two specific biological systems which were selected for the distinct characteristics of their assembly, and their relevance to human health. This will test the central hypothesis that molecular assembly is enhanced by the organization of the plasma membrane in the form of cytoskeletal elements and protein-lipid platforms. This interdisciplinary research will provide an experimental foundation for a statistical description of the cell, whose behaviour is embedded in protein organization and dynamics.
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