Regulation of vesicular membrane traffic by ARF proteins

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Bi-directional vesicular traffic is required to secrete proteins, to internalize proteins, and to generate the asymmetries in lipid and protein composition that underlie organellogenesis, cell growth and differentiation. Membrane traffic is a complex process that requires integration with virtually every other cell function, including the cell cycle, protein synthesis, ribosome assembly, and lipid metabolism. While a complete loss of such a highly integrated process would damage cells irreparably, more subtle defects in membrane traffic impact a number of human diseases, including Alzheimer's disease, cystic fibrosis, and others. The recruitment of distinct protein coat complexes is a first step in the construction of specific vesicles involved in membrane traffic. ADP-ribosylation factors (ARFs) are GTPases and regulators of vesicular traffic, though the molecular mechanisms are still only incompletely understood. We discuss a model to explain the role of ARF in a homologous vesicle budding reactions that reinforces the idea that the recruitment of soluble proteins to the bud is the initiating and/or rate-limiting step in vesicle biogenesis in membrane traffic. We propose that a minimum of three components (ARF, a transmembrane docking site, and an adaptor or coat complex) are required for formation of vesicles emanating from the Golgi/TGN. Seven of these ARF-dependent coat complexes have been described. Because all of these adaptors are recruited to Golgi/TGN membranes by ARF we sought a regulatory mechanism that could provide added levels of regulation and specificity of vesicle budding from a common membrane source. We further propose that protein phosphorylation acts in concert with cycles of ARF activation/inactivation through regulated GTP binding to regulate vesicle biogenesis or specificity. We propose to test the hypothesis that MlNTs represent a novel family of ARF-dependent adaptors involved in vesicle budding from the Golgi/TGN and that the Alzheimer's protein (amyloid precursor protein; APP) is the transmembrane protein that docks the ARF-MINT complex to membranes. This provides a model for the physiological role of APP in our cells and is likely to lead to a better understanding of the pathophysiology resulting from the secretion of proteolytic products of APP that occurs in Alzheimer's disease.