PRE-MRNA SPLICE SITE RECOGNITION IN HUMAN DISEASE

人类疾病中的前 mRNA 剪接位点识别

• 批准号: 8362272
• 负责人: CLARA KIELKOPF
• 金额: $ 0.03万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362272
• 关键词: Binding; Complex; Disease; Foundations; Funding; Goals; Grant; Inherited; Light; National Center for Research Resources; Phosphorylation; Principal Investigator; RNA Splicing; Radiation; Research; Research Infrastructure; Resources; Signal Transduction; Site; Source; Staging; Structure; United States National Institutes of Health; Work; cost; human disease; mRNA Precursor; novel; structural biology; three dimensional structure

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The overall goal of our research is to understand the three-dimensional structures that guide pre-mRNA splicing, and to thereby provide a foundation to develop treatments for inherited diseases associated with errors in splice site recognition. During the critical early stages of splice site choice, the essential splicing factor U2AF cooperatively recognizes the pre-mRNA splice site as a complex with Splicing Factor 1 (SF1). This interaction is regulated by phosphorylation of key SF1 domain that contributes to U2AF binding, but lacks detectable homology with known structures. The primary aim of the proposed work is to determine the crystal structure of this key SF1 domain. The novel structure of this SF1 domain would shed light on the means of action by this important splicing factor. In addition, we recently obtained crystals of the phosphorylated state of the SF1 domain, which would reveal signal-dependent conformational changes.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 我们研究的总体目标是了解指导前mRNA剪接的三维结构，从而为开发与剪接位点识别错误相关的遗传性疾病的治疗方法提供基础。在剪接位点选择的关键早期阶段，必需剪接因子U2 AF与剪接因子1（SF 1）合作识别前mRNA剪接位点作为复合物。这种相互作用是由关键SF 1结构域的磷酸化调节的，该结构域有助于U2 AF结合，但与已知结构缺乏可检测的同源性。所提出的工作的主要目的是确定这个关键的SF 1域的晶体结构。这个SF 1结构域的新颖结构将揭示这个重要剪接因子的作用方式。 此外，我们最近获得了SF 1结构域的磷酸化状态的晶体，这将揭示信号依赖的构象变化。