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人类DOT1L的催化域的结构,一个非SET域的核体组合组合基因组甲基转移酶
Jinrong Min1, Qin Feng, Zhizhong Li
1W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Cell
|March 12, 2003
概括
研究人员阐明了人类Dot1-like (hDOT1L) 的结构,这是一个独特的基因组甲基转移酶. 这项研究揭示了hDOT1L.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- Dot1是一种保守的组分离子甲基转移酶,负责在lysine-79.9处甲基化组分离子H3.
- 与其他已知的基因组甲基转移酶不同,Dot1缺乏SET域,并专门针对核细胞组基因组H3.
- 了解Dot1的独特机制对于了解表观遗传调节至关重要.
研究的目的:
- 确定与S-adenosyl-L-methionine (SAM) 复合的人类Dot1-like (hDOT1L) 的催化域的高分辨率晶体结构.
- 阐明hDOT1L独特的催化机制的结构基础及其对核细胞基质的特异性.
- 为Dot1蛋白在表观遗传调节中的功能提供机制性见解.
主要方法:
- 使用X射线晶体学解决了hDOT1L催化域与SAM结合的2.5 Å分辨率结构.
- 进行了生物化学测试,以评估不同蛋白质区域在核细胞结合和酶活性中的作用.
- 用分子建模来进一步研究催化机制和基质特异性.
主要成果:
- 解决的结构揭示了hDOT1L的独特架构,其中包括一个alpha-helical N-terminal域和一个中央的alpha/beta结构.
- 关键的结构特征包括定义的SAM结合口袋和氨酸基质结合的潜在通道.
- 一个灵活的,正电荷的C端区域被确定为核细胞结合和催化活动的关键.
结论:
- 结构和生化数据为hDOT1L作为基因素甲基转移酶的功能提供了重要的机械洞察力.
- 这些发现突出了Dot1蛋白质独特的结构组织和基质识别机制.
- 这项研究促进了我们对这种重要的表观遗传调节器的催化机制和核细胞特异性的理解.
相关概念视频
02:10The Nucleosome Core Particle
Nucleosomes are the DNA-histone complex, where the DNA strand is wound around the histone core. The histone core is an octamer containing two copies of H2A, H2B, H3, and H4 histone proteins.
The paradox
Nucleosomes, paradoxically, perform two opposite functions simultaneously. On the one hand, their main responsibility is to protect the delicate DNA strands from physical damage and help achieve a higher compaction ratio. While on the other hand, they must allow polymerase enzymes to access DNA...
The paradox
Nucleosomes, paradoxically, perform two opposite functions simultaneously. On the one hand, their main responsibility is to protect the delicate DNA strands from physical damage and help achieve a higher compaction ratio. While on the other hand, they must allow polymerase enzymes to access DNA...
02:32Histone Modification
The histone proteins have a flexible N-terminal tail extending out from the nucleosome. These histone tails are often subjected to post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination. Particular combinations of these modifications form “histone codes” that influence the chromatin folding and tissue-specific gene expression.
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
02:38Heterochromatin
The extent of chromatin compaction can be studied by staining chromatin using specific DNA binding dyes. Under the microscope, the dense-compacted regions that take up more dye are called heterochromatin. Heterochromatin is further classified into two forms – constitutive heterochromatin and facultative heterochromatin.
Constitutive heterochromatin: It is a highly compact region of chromatin that is mostly concentrated in the centromere and telomere. Unlike euchromatin, the amino acid at 9th...
Constitutive heterochromatin: It is a highly compact region of chromatin that is mostly concentrated in the centromere and telomere. Unlike euchromatin, the amino acid at 9th...
02:32Histone Modification
The histone proteins have a flexible N-terminal tail extending out from the nucleosome. These histone tails are often subjected to post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination. Particular combinations of these modifications form “histone codes” that influence the chromatin folding and tissue-specific gene expression.
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
01:19The Nucleosome
Human DNA is almost two meters long. However, it is compressed inside a tiny nucleus measuring only a few microns in diameter. To make this degree of compaction possible, DNA is organized into several sequential levels so that it can fit into such a tiny space. The most compact form of DNA is a chromosome that can be seen under a microscope in a dividing cell.
In a chromosome, DNA is wound twice around a protein complex called a histone octamer core, which consists of 8 histone proteins. This...
In a chromosome, DNA is wound twice around a protein complex called a histone octamer core, which consists of 8 histone proteins. This...
01:12The Nucleosome Core Particle
Nucleosomes are the DNA-histone complex, where the DNA strand is wound around the histone core. The histone core is an octamer containing two copies of H2A, H2B, H3, and H4 histone proteins.
Nucleosomes, paradoxically, perform two opposite functions simultaneously. On the one hand, their primary aim is to protect the delicate DNA strands from physical damage and help achieve a higher compaction ratio. On the other hand, they must allow polymerase enzymes to access histone-bound DNA during...
Nucleosomes, paradoxically, perform two opposite functions simultaneously. On the one hand, their primary aim is to protect the delicate DNA strands from physical damage and help achieve a higher compaction ratio. On the other hand, they must allow polymerase enzymes to access histone-bound DNA during...