Regulation of vesicular membrane traffic by ARF proteins

描述(申请人提供)：需要双向囊泡运输来分泌蛋白质，内化蛋白质，并产生构成器官发生、细胞生长和分化的脂肪和蛋白质组成的不对称。膜运输是一个复杂的过程，需要整合几乎所有其他细胞功能，包括细胞周期、蛋白质合成、核糖体组装和脂质代谢。虽然完全失去这种高度整合的过程会对细胞造成不可修复的损害，但膜运输中更微妙的缺陷会影响许多人类疾病，包括阿尔茨海默病、囊性纤维化等。招募不同的蛋白质包膜复合体是构建参与膜运输的特定囊泡的第一步。ADP-核糖化因子(ARF)是GTP酶和囊泡运输的调节者，但其分子机制仍不完全清楚。我们讨论了一个模型来解释ARF在同源囊泡发芽反应中的作用，该模型强化了可溶性蛋白招募到芽中是膜运输中囊泡生物发生的启动和/或速率限制步骤的想法。我们认为，至少需要三种成分(ARF、跨膜对接位置和适配器或涂层复合体)来形成来自高尔基体/TGN的囊泡。其中七种依赖于ArF的涂层络合物已被描述。由于所有这些接头都是通过ARF招募到高尔基体/TGN膜上的，我们寻求一种调节机制，可以提供更高水平的调节和来自共同膜来源的囊泡出芽的特异性。我们进一步提出，通过调节GTP结合，蛋白质磷酸化与ARF激活/失活循环协同作用，调节囊泡的生物发生或特异性。我们建议检验这样一种假设，即MlNTs代表一种新的ARF依赖的适配器家族，参与高尔基体/TGN的囊泡萌发，而阿尔茨海默氏症蛋白(淀粉样前体蛋白；APP)是将ARF-MINT复合体对接到膜上的跨膜蛋白。这为APP在细胞中的生理作用提供了一个模型，并可能导致更好地理解发生在阿尔茨海默病中的APP蛋白分解产物的分泌所导致的病理生理学。

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.