MOLECULAR MECHANISM OF HISTONE ACETYLATION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 真核DNA被包装在核小体颗粒中，以便在细胞核内组装成高阶结构。在许多蛋白质复合体介导的模式中，组蛋白修饰对于几乎所有的DNA相关过程都是重要的。根据核小体构象改变或染色质构象改变，染色质重塑复合体可以分为两类。组蛋白乙酰化负责染色质构象改变，而组蛋白乙酰转移酶(HATS)是大的多蛋白复合体的催化亚单位，它对组蛋白的N末端尾部进行乙酰化以促进真核生物中的转录激活。蛋白质-蛋白质复合体介导组蛋白修饰的结构基础是理解这些过程的关键。尽管在过去的十年中，在理解组蛋白翻译后修饰(包括乙酰化、磷酸化、甲基化和泛素化)方面取得了重大的结构进展[文献4]，但仍然有许多问题没有得到回答：例如组蛋白尾部有多少个修饰热点，有多少不同的结构模块可以识别一个组蛋白修饰，一个结构模块可以识别多少不同的组蛋白修饰位点，有多少个结构模块可以组合来识别一个组蛋白修饰。从长远来看，我想以几个关键的组蛋白超复合体为目标，从结构和分子的角度回答所有这些基本问题。在这个提议中，我概述了以下结构和生化方法的组合，以研究与组蛋白编码相关的蛋白质-肽识别和蛋白质-蛋白质相互作用事件，例如Rtt109复合体介导的H3K56乙酰化和NuA4复合体介导的H4K16乙酰化

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. Eukaryotic DNA is packed in nucleosomal particles for assembly into high-order structures in the nucleus. Histone modifications in patterns mediated by numerous protein complexes are important for almost all DNA-related processes. Chromatin remodelling complexes can be grouped into two categories depending on nucleosomal conformational alteration or chromatin conformational alteration.Histone acetylation is responsible for chromatin conformational alteration, while Histone acetyltransferases (HATs) are the catalytic subunits of large multiprotein complexes that acetylate the N-terminal tail regions of histones to facilitate transcription activation in eukaryotes.Structural bases for histone modifications mediated by protein-protein complexes are critical to understand these processes. Although during past one decade, significant structural progresses are obtained to understand histone posttranslational modifications including acetylation, phosphorylation, methylation and ubiquitination [reviewed in 4], there are still a lot of unanswered questions: such as how many hotspots exist for modification within histone tails, how many different structural modules can recognize one single histone modification, how many different histone modification sites a single structural module can recognize, how many structural modules can be combined to recognize one single histone modification. In the long term, I would like to answer all these fundamental questions from the structural and molecular view by targeting several critical histone supercomplexes. At this proposal, I outline below a combination of structural and biochemical approaches to study protein-peptide recognition and protein-protein interaction events associated with Histone Code, such as Rtt109 complex mediated H3K56 acetylation and NuA4 complex mediated H4K16 acetylation