Structural Biology of Sin3 Corepressor

Sin3 辅阻遏物的结构生物学

• 批准号: 6620796
• 负责人: Ishwar Radhakrishnan
• 金额: $ 24.54万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620796
• 关键词: amidohydrolases; calorimetry; conformation; eukaryote; gene induction /repression; genetic transcription; nuclear magnetic resonance spectroscopy; protein binding; protein protein interaction; protein purification; protein sequence; structural biology; thermodynamics; transcription factor

DESCRIPTION (provided by applicant): Regulation of eukaryotic gene expression at the transcriptional level relies on the coordinated action of multiple protein factors. Recruitment of multi-protein cofactor complexes containing chromatin-modifying and/or chromatin-remodeling activities by sequence-specific DNA binding factors appears to be a common, highly conserved mechanism of regulating gene transcription at many promoters. The Sin3 corepressor complex is one of two major repression machineries identified thus far in mammalian cells. The negative influence on gene transcription exerted by these corepressor complexes is thought to rely in part on the action of histone deacetylases (HDACs), a group of enzymes that catalyze the hydrolysis of acetyl groups from acetylated histone substrates. The Sin3 corepressor functions as a molecular adapter specifically associating with HDAC1 and HDAC2 on the one hand and a surprisingly large and diverse group of transcription factors that play crucial roles in normal development on the other. The structural basis for such macromolecular associations, which has important implications in the strict regulation of gene transcription, is poorly understood. Our studies will address fundamental questions including, how Sin3 interacts with its targets at the atomic level, why it interacts specifically with these targets but not with others, and which residues make important contributions towards the stability of these macromolecular associations. Answers to these questions rely largely on detailed structure-function analyses. Our primary tool for these investigations will be high-resolution liquid-state NMR spectroscopy but we will also pursue biochemical and other biophysical approaches, as necessary.

描述（由申请人提供）：真核基因表达的调节 在转录级别，依赖于多个的协调作用 蛋白质因子。募集包含的多蛋白辅因子络合物 通过序列特异性的染色质修饰和/或染色质复制活性 DNA结合因子似乎是一种常见的高度保守机制 调节许多启动子的基因转录。 SIN3 COREPRESSOR综合体 是迄今为止在哺乳动物中确定的两个主要压抑机器之一 细胞。这些对基因转录的负面影响 人们认为Corepressor络合物部分依赖于组蛋白的作用 脱乙酰基酶（HDACS），一组酶，可催化乙酰水解 来自乙酰化组蛋白底物的基团。 SIN3 COREPRESSOR充当 一方面，分子适配器与HDAC1和HDAC2专门关联 以及一个出乎意料的大型和多样化的转录因子群 在正常发展中的关键作用。这样的结构基础 大分子关联，这对严格的含义具有重要意义 基因转录的调节知之甚少。我们的研究将 解决了基本问题，包括SIN3如何与其目标相互作用 原子层，为什么它专门与这些目标进行交互 其他以及哪些残留物为稳定做出重要贡献 这些大分子关联。这些问题的答案很大程度上依赖 关于详细的结构功能分析。我们为这些的主要工具 研究将是高分辨率液态NMR光谱法，但我们 必要时还将采用生化和其他生物物理方法。