Biogenesis of Dense Core Secretory Granules in Tetrahymena

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DESCRIPTION (provided by applicant): Dense core secretory granules are vesicles that are responsible for storage and regulated release of a wide variety of polypeptides including hormones, digestive enzymes, and peptide neurotransmitters. Granules store their contents in the cytoplasm of specialized cell types and release these only in graded response to extracellular stimuli. Genetic and environmentally-induced lesions in granule function are connected with serious human diseases, including diabetes and developmental problems. Nonetheless our understanding of the pathway responsible for granule synthesis is still missing important details. The function of secretory granules requires that the specific cargo polypeptides are sorted to vesicles together with membrane proteins that facilitate vesicle docking and fusion. Protein sorting must take place in the trans-Golgi network, but the mechanisms involved are not known. Furthermore, the proteins involved in docking and fusion may be localized to particular regions of the secretory granule membrane. Our aim is to understand the molecular bases for the organization of granule membrane proteins both during sorting and in the fully-formed granule. We will do this using the ciliate Tetrahymena thermophila, a genetically-manipulable single-celled system. We have discovered several proteins within Tetrahymena secretory granules that are strong candidates for components interacting with membrane proteins, and we will use a combination of biochemistry and genetics to dissect their function.