Regulation of Nuclear Import Through Importin Alpha Isoforms

项目摘要 大分子在细胞核和细胞质之间的运输是一项基本的细胞功能。 与导致疾病的许多退化过程密切相关，并正在成为一个有希望的目标 进行治疗干预。在过去的30年里，细胞、分子和结构生物学取得了巨大的进步 在阐明核运输的“设计原则”方面发挥了重要作用。临界溶解因子 已查明通过核孔复合体(NPC)贩运货物。该组织， 酵母NPC的结构和组装已被揭示。支配通过的物理原理 通过全国人大的大分子已经被破译。与此形成鲜明对比的是，人们对 核运输的调节和导致时空调节的“微调”机制 细胞核中关键信号分子的可用性。在这项提议中，通过整合生物物理学， 通过生化和功能技术，我们试图了解导入接头的亚型如何在α中导入 调控核输入的关键因子是NF-κB和RAN信号通路。具体来说，我们建议： 1)生理条件下NF-αB异构体对Importinκ异构体选择性作用机制的研究 条件和疾病状态；2)破译Importinα3如何调制四元结构和 RCC1进口复合体的运输特性。总体而言，我们的工作将揭示一个鲜为人知的 核运输一章，目的是利用大自然的复杂规则来识别小说 药理靶标。

Project Summary Trafficking of macromolecules between the nucleus and the cytoplasm is an essential cellular function intimately linked to many degenerative processes that lead to disease and is emerging as a promising target for therapeutic intervention. Over the last 30 years, dramatic progress in cell, molecular and structural biology has been instrumental in elucidating the `design principles' of nuclear transport. Critical soluble factors trafficking cargos through the Nuclear Pore Complex (NPC) have been identified. The organization, architecture and assembly of the yeast NPC has been revealed. The physical principles governing passage of macromolecules through the NPC have been deciphered. In stark contrast, far less is known about the regulation of nuclear transport and the mechanisms of `fine-tuning' that result in spatiotemporally regulated availability of critical signaling molecules in the cell nucleus. In this proposal, by integrating biophysical, biochemical and functional techniques, we seek to understand how isoforms of the import adaptor importin α regulate nuclear import of key factors of the NF-κB and Ran signaling pathways. Specifically, we propose to: 1.) Determine the mechanisms of importin α isoform selectivity for NF-κB heterodimers under physiological conditions and in disease states; 2.) Decipher how importin α3 modulates the quaternary structure and transport properties of the RCC1 import complex. Overall, our work will shed light on a poorly understood chapter of nuclear transport, with the goal of exploiting nature's complex regulation to identify novel pharmacological targets.