The overall goal of this Program Project is to understand the molecular mechanisms involved in the control of protein and membrane traffic in eukaryotic cells from the site of synthesis in the endoplasmic reticulum (ER), through the Golgi, to the cell surface and through the endocytic pathway. Quality control in the secretory pathway. Project III will utilize several approaches to address questions concerning the mechanism of glycoprotein folding, oligomeric assembly and quality control. The retrograde transport pathway from the Golgi to the ER will be defined and the role of the golgi in quality control will be addressed. Characterization of Geranylgeranyltransferase Type II. Project II concerns the role of isoprenylation in the function of the GTP-binding protein, Ypt1. The geranylgeranyltransferase will be purified and characterized. Proteins that interact with Ypt1 will be identified and the role of isoprenylation in these interactions will be addressed. Regulation of exocytosis by Sec4 and accessory proteins. Project VII will analyze the interaction between Sec4 and the accessory proteins which control the rate of nucleotide exchange, the rate of nucleotide hydrolysis, the specificity of Sec4 membrane attachment and the recycling of Sec4 through the cytoplasm. Biogenesis of regulated secretion in exocrine pancreas. Project V will explore the hypothesis that the appearance of a zymogen granule associated protein of the Sec4/Ypt1/rab family or one of the accessory proteins is the limiting factor regarding stimulus-secretion coupling in the exocrine pancreas of prenatal rats. Rab proteins and exo-endocytosis in neuroendocrine cells. Project I concerns the role of the endosome in the biogenesis and recycling of synaptic vesicles (SV) in neurons and synaptic-like microvesicles (SLMV) in endocrine cells. the role of rab proteins and their accessory proteins in biogenesis and recycling will be probed. Rab proteins in synaptic vesicle exocytosis and recycling. Project IV concerns the role of several rab proteins and their accessory proteins in the exocytosis and recycling associated with synaptic transmission. The role of GTP hydrolysis by rab3A and rab5 will be defined. GTP-binding proteins and endocytosis. Project VI concerns the role of rab4 in receptor-mediated endocytosis and the molecular mechanisms underlying the reversible arrest of endocytosis in mitotic cells. The interaction of rab4 with accessory proteins will be measured as a function of the cell cycle dependent phosphorylation of rab4 by the cdc2 protein kinase.
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