MOLECULAR MECHANISM OF HISTONE ACETYLATION

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 真核DNA被包装在核小体颗粒中，用于组装成细胞核中的高级结构。组蛋白修饰的模式介导的许多蛋白质复合物是重要的，几乎所有的DNA相关的过程。根据核小体构象改变或染色质构象改变，染色质重构复合物可分为两类。 组蛋白乙酰化是导致染色质构象改变的重要因素，而组蛋白乙酰转移酶（HAT）是多蛋白复合物的催化亚基，能乙酰化组蛋白的N-末端尾区，促进真核生物的转录激活。 蛋白质-蛋白质复合物介导的组蛋白修饰的结构基础对于理解这些过程至关重要。虽然在过去的十年中，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[4]，但仍然有很多未回答的问题：例如在组蛋白尾部存在多少修饰热点，有多少不同的结构模块可以识别一个单一的组蛋白修饰，单个结构模块可以识别多少不同的组蛋白修饰位点，多少结构模块可以组合以识别单个组蛋白修饰。从长远来看，我想通过针对几个关键的组蛋白超复合物，从结构和分子的角度回答所有这些基本问题。在此基础上，我提出了一种结合结构和生物化学的方法来研究与组蛋白密码相关的蛋白质-肽识别和蛋白质-蛋白质相互作用事件，如Rtt 109复合物介导的H3 K56乙酰化和NuA 4复合物介导的H4 K16乙酰化

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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