MOLECULAR BASIS OF RAN MEDIATED NUCLEAR TRANSPORT

本提案的广泛长期目标是了解 Ran GT驱动大分子的双向运动， 核膜有证据表明，冉合作， 一些辅助蛋白质将蛋白质移入和移出细胞， 原子核这项建议的具体目标是：1）审查在 Ran功能所必需的体内相互作用; 2）测试 假设Ran-GDP结合的基本细胞作用 蛋白质，核转运因子2（NTF 2）是浓缩Ran-GDP在 核孔，需要Ran启动核输入;以及 3)使用遗传学方法来确定核孔上的位点 代表NTF 2的对接位点，最有可能是NTF 2- 很复杂。拟议的研究使用芽殖酵母 酿酒酵母作为体内遗传和细胞生物学模型 实验和扩展到生物化学研究，体内功能 研究和细胞生物学实验，并扩展到生物化学 研究、体内功能研究和结构研究， 酵母蛋白和它们高度保守的人类对应物。的 这项建议与健康有关是双重的。第一，激活信号 信号转导通路向细胞核发送信号， 刺激并激活转录。这是最经常实现的 通过蛋白质进入细胞核。这方面的信号 经常被忽视或轻视，但它可能代表了一个未被利用的 靶向阻断特定的细胞信号以及 在转化细胞中产生的不受调节的信号。第二，病毒 利用内源性核转运 机械既能进入原子核， 他们自己复制的遗传物质更详细地理解 调节核运输的机制可能提供新的靶点 用于抗病毒治疗。

The broad long term objective of this proposal is to understand how the Ran GTPase drives bi-directional movement of macromolecules across the nuclear envelope. There is evidence to suggest that Ran cooperates with a number of accessory proteins to move proteins into and out of the nucleus. The specific aims of this proposal are: 1) to examine the in vivo interactions that are essential for Ran function; 2) to test the hypothesis that the essential cellular role of the Ran-GDP binding protein, nuclear transport factor 2 (NTF2) is to concentrate Ran-GDP at the nuclear pore, where Ran is required to initiate nuclear import; and 3) to use a genetic approach to define the site(s) on the nuclear pore that represent(s) the docking site for NTF2 and most probably the NTF2- Ran complex. The proposed studies use the budding yeast Saccharomyces cerevisiae as a model for in vivo genetic and cell biological experiments and extend to biochemical studies, in vivo functional studies, and cell biological experiments and extend to biochemical studies, in vivo functional studies, and structural studies of both the yeast proteins and their highly conserved human counterparts. The health-relatedness of this proposal is two-fold. First, activated signal transduction pathways send a signal to the nucleus in order to respond to stimuli and activate transcription. This is most often accomplished by the movement of a protein into the nucleus. This aspect of signaling is often ignored or trivialized, yet it may represent an unexploited targeted for blocking specific cellular signals as well as the unregulated signals that arise in transformed cells. Second, viruses that infect human cells exploit the endogenous nuclear transport machinery both to gain entry to the nucleus and later to rapidly export their own replicated genetic material. A more detailed understanding of the machinery that mediates nuclear transport may provide novel targets for anti-viral therapies.