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Architecture of the Diffusion Barrier in the Nuclear Pore Complex

核孔复合体中扩散势垒的结构

基本信息

批准号：
7683744
负责人：
MICHAEL F REXACH
金额：
$ 33.31万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-28 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7683744
关键词：
Adopted Amino Acids Animal Model Architecture Asses Behavior Binding Biochemical Biochemistry Biological Biological Assay Biophysics Caliber Cell Nucleus Cells Cellular biology Collection Communication Cytoplasm Cytoplasmic Protein Diffusion Disease Environment Eukaryota Family Filament Gatekeeping Genes Genetic Genetic Materials Glycine Health Human In Situ In Vitro Individual Knowledge Learning Life Locales Location Malignant Neoplasms Maps Molecular Molecular Machines Molecular Models Names Nuclear Magnetic Resonance Nuclear Pore Complex Nuclear Pore Complex Proteins Nucleoplasm Operative Surgical Procedures Permeability Phenylalanine Proteins Recombinants Research Role Saccharomyces cerevisiae Scientist Shapes Solutions Structure Techniques Technology Tertiary Protein Structure Testing Yeasts aqueous flexibility genetic manipulation in vivo insight molecular modeling nanometer novel particle porin professor protein function receptor research study seal structural biology three dimensional structure trafficking

项目摘要

The nuclear pore complex (NPC) is one of the most important molecular machines in eukaryotes because it gates the porous conduits between the cytoplasm and nucleoplasm of cells and controls all nucleo-cytoplasmic traffic and communication. Its most important architectural feature is a poorly understood semi-permeable diffusion barrier in its center that maintains a tight seal against cytoplasmic proteins as small as 4 nanometers in size, but opens to allow facilitated transport of particles of all shapes and sizes up to 40 nanometers in size. This flexible barrier is composed of a family of filamentous proteins named FG nucleoporins (FG nups) that feature large unfolded domains in their native functional state, which are decorated with multiple phenylalanine glycine motifs (FG domains). The specific aims of our proposed research are to 1) characterize the dynamic structure and intra-molecular interactions of FG domains representing two different types of FG nup filaments that are anchored at three different locales of the NPC, and 2) test the hypothesis that inter-molecular associations between FG domains of nups create a filamentous meshwork structure at the NPC center, which establishes the size-selective barrier to the passive diffusion of proteins. The proposed experiments will combine biochemical, biophysical, cell biological, structural (Nuclear Magnetic Resonance), and molecular modeling techniques to gain insight into the dynamic behavior, structure and function of the FG nups. We will also gain fundamental knowledge on the dynamic behavior and structure of disordered domains of proteins in general. We are studying the three-dimensional structure of the cellular proteins that function as gatekeepers of our genetic material in the nucleus. Their proper architecture and function is vital to human health because they control the flow of information to and from our genes. When they fail to function normally, these proteins can trigger the onset of cancer. We wish to understand how their structure enables them to function as gatekeepers of the nucleus.

核孔复合物（NPC）是一种重要的生物分子，在真核生物中是一种机器，因为它控制着细胞质之间的多孔管道，和细胞核质，并控制所有的核质运输和通信。其最重要的建筑特征是一个鲜为人知的半渗透扩散在它的中心有一个屏障，对小到4 纳米大小，但开放，以允许所有形状的颗粒，尺寸可达40纳米。这种柔性屏障由一系列称为FG核孔蛋白（FG nups）的丝状蛋白，其特征在于大的未折叠的结构域在其天然功能状态下，其被多个苯丙氨酸修饰甘氨酸基序（FG结构域）。我们提出的研究的具体目标是：1）表征动态代表两种不同类型的FG结构域的结构和分子内相互作用固定在NPC的三个不同部位的FG nup细丝，以及2）测试 nups的FG结构域之间的分子间缔合产生一种在NPC中心的丝状网状结构，这建立了大小选择性蛋白质被动扩散的屏障。拟议的实验将联合收割机生物化学、生物物理学、细胞生物学、结构（核磁共振），以及分子模拟技术，以深入了解动态行为，结构和 FG nups的功能。我们还将获得有关动态的基本知识蛋白质无序结构域的行为和结构。我们正在研究细胞蛋白质的三维结构，细胞核中遗传物质的守门人。它们的结构和功能对人类健康至关重要，因为它们控制着信息的流动，我们的基因当它们不能正常发挥功能时，这些蛋白质会引发癌我们希望了解它们的结构如何使它们能够发挥作用原子核的守门人