The project aims to elucidate key biophysical mechanisms underlying clathrin-mediated endocytosis in yeast. Endocytosis involves a network of over sixty proteins, which exert forces that deform the cell membrane. The protein actin, whose polymerization is controlled by upstream proteins called nucleation-promoting-factors, plays a major role in generating force and controlling protein assembly. We will explore the functionality of the endocytic protein network, and the mechanisms by which force is generated, through mathematical modeling, simulation and quantitative experimental studies. The mathematical methods include stochastic simulation of actin polymerization, and a finite- element approach to membrane deformation. The experimental methods include actin polymerization assays and high-resolution imaging of key endocytic proteins. The experimental outputs will be compared directly to the theoretical predictions. The combination of theory and experiment will explain how multiple nucleation promoting factors regulate actin polymerization;how different nucleation-promoting factors become segregated to different parts of the endocytic tubule;and how the spatial distribution of forces leading to endocytosis is regulated by actin and curvature-generating proteins. Because of its small spatial scale, and the limited number of proteins involved, clathrin- mediated endocytosis is a model process for understanding the function of intracellular mechanochemical networks - networks where chemistry is coupled bidirectionally to force generation and membrane deformation. Therefore our understanding of endocytosis will help us understand the more complex mechanochemical networks in cells, such as those driving ruffling, lamellipodium or filopodium formation, and cell migration.
This research project is relevant to public health because endocytosis impacts a broad range of diseases including (i) Alzheimer's disease, where endocytosis plays a key role in the production of a key peptide, and (ii) cancer, where endocytosis controls the number of key receptor molecules. Thus, understanding the mechanisms of endocytosis in detail could impact our understanding of a broad range of cellular phenomena and diseases.
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