Regulation of Nuclear Import Through Importin Alpha Isoforms

通过导入α亚型来调节核进口

基本信息

批准号：
10083745
负责人：
Gino Cingolani
金额：
$ 32.76万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10083745
关键词：
3-Dimensional Active Biological Transport Adopted Affect Amino Acid Sequence Architecture Binding Biochemical Biology Biophysics Cell Nucleus Cell physiology Cellular biology Chromatin Complex Cytoplasm Data Disease Ebola Eukaryotic Cell Genes Goals Guanine Guanine Nucleotide Exchange Factors Human Genome Importins In Vitro Individual Inflammatory Response Influenza Karyopherins Lead Light Link Malignant Neoplasms Maps Mediating Molecular Biology Molecular Conformation Monomeric GTP-Binding Proteins N-terminal NF-kappa B Nature Nuclear Import Nuclear Localization Signal Nuclear Pore Complex Pathogenicity Pathway interactions Peptide Signal Sequences Pharmacology Physiological Post-Translational Protein Processing Process Property Protein Isoforms Proteins Publishing Regulation Research Research Project Grants Route Signal Pathway Signaling Molecule Simian virus 40 Specificity Structure System TNFRSF5 gene Techniques Testing Therapeutic Intervention Up-Regulation Viral Proteins Work Yeasts alpha Karyopherins base carcinogenesis design flexibility human disease in vivo macromolecule novel nucleocytoplasmic transport nucleoplasmin p65 rat Ran 2 protein receptor recruit spatiotemporal structural biology targeted treatment three dimensional structure trafficking transcription factor transcriptome

项目摘要

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.

项目概要细胞核和细胞质之间大分子的运输是一项重要的细胞功能与许多导致疾病的退行性过程密切相关，并且正在成为一个有希望的目标过去 30 年来，细胞、分子和结构生物学取得了巨大进展。在阐明核运输的“设计原则”方面发挥了重要作用。已查明通过核孔复合体（NPC）进行的货物贩运。酵母 NPC 的结构和组装已被揭示。与此形成鲜明对比的是，人们对NPC的了解却少之又少。核运输的调节和导致时空调节的“微调”机制在该提案中，通过整合生物物理，获得细胞核中关键信号分子的可用性。生化和功能技术，我们试图了解导入接头的亚型如何导入α 调节 NF-κB 和 Ran 信号通路关键因子的核输入具体来说，我们建议： 1.) 确定生理条件下NF-κB异二聚体输入α亚型选择性的机制条件和疾病状态；2.) 破译输入蛋白 α3 如何调节四级结构和总体而言，我们的工作将揭示一个人们知之甚少的 RCC1 进口综合体的运输特性。核运输的章节，目标是利用自然的复杂调节来识别新的药理靶点。