ヒトのNuA4/TIP60アセチルトランスフェラーゼとクロマチンの改造複合体に関する構造的洞察

Zhenlin Yang^1,2, Amel Mameri³, Claudia Cattoglio^2,4

¹California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, CA, USA.

Science (New York, N.Y.)

|August 1, 2024

まとめ

遺伝子調節とゲノム安定性にとって重要なNuA4/TIP60複合体は,EP400を支柱として使用しています. TRRAPの損失は,H2A.Zの分布とアセチル化を妨害し,複合体を強調する

科学分野:

分子生物学
エピジェネティクス
構造生物学

背景:

NuA4/TIP60複合体はヒストンをアセチル化し,H2A.Zを組み込み,遺伝子発現とゲノム安定性を調節する.
この複合体は酵母 SWR1とNuA4複合体の融合であり,その進化的重要性を強調しています.

研究の目的:

NuA4/TIP60複合体の構造的組織を解明する.
複雑な組み立てと機能における EP400サブユニットの役割を理解する.
複合的な局所化とヒストンの改変に対するTRRAPサブユニット喪失の影響を調査する.

主な方法:

クリオ電子顕微鏡 (cryo-EM) を用いて,NuA4/ TIP60複合体の構造を決定した.
亜単位の相互作用と複合体の形成を分析するために生化学的測定法を使用した.
H2A.Zの分布とアセチル化を評価するために全ゲノム分析が行われました.

主要な成果:

Cryo-EMは,EP400サブユニットが,ARPモジュールを含む機能モジュールを組織する支架として機能することを明らかにしました.
EP400のTRRAPへの結合は,SAGA複合体との相互作用を防止し,ハイブリッド複合体の形成を阻害する.
TRRAPの喪失は,NuA4/TIP60の誤局化と,ゲノム全体でのH2A.Zの分布とアセチル化の変化をもたらした.

結論:

EP400サブユニットは,NuA4/TIP60複合体の構造的整合性と特殊な配置に不可欠です.
局所化におけるTRRAPの役割は,H2A.Zの堆積とアセチル化におけるNuA4/TIP60の適切な機能に不可欠である.
NuA4/TIP60は,遺伝子調節とゲノム安定性における二重の役割を担う単一のマクロ分子組成として機能する.

さらに関連する動画

10:14

Biochemical Assays for Analyzing Activities of ATP-dependent Chromatin Remodeling Enzymes

Published on: October 25, 2014

14.8K

06:32

Deciphering Molecular Mechanism of Histone Assembly by DNA Curtain Technique

Published on: March 9, 2022

1.8K

関連する概念動画

02:54

Nucleosome Remodeling

9.1K

Nucleosomes are the basic units of chromatin compaction. Each nucleosome consists of the DNA bound tightly around a histone core, which makes the DNA inaccessible to DNA binding proteins such as DNA polymerase and RNA polymerase. Hence, the fundamental problem is to ensure access to DNA when appropriate, despite the compact and protective chromatin structure.
Nucleosome remodeling complex
Eukaryotic cells have specialized enzymes called ATP-dependent nucleosome remodeling enzymes. These enzymes...

9.1K

01:32

Chromatin Modification in iPS Cells

1.6K

Chromatin modification alters gene expression; therefore, scientists can add histone-modifying enzymes, histone variants, and chromatin remodeling complexes to somatic cells to aid reprogramming into pluripotent stem (iPS) cells.
Compact chromatin makes reprogramming difficult. Enzymes, such as histone demethylases and acetyltransferases, are often added during reprogramming to loosen the chromatin, making the DNA more accessible to transcription factors. Molecules that inhibit histone...

1.6K

02:25

Spreading of Chromatin Modifications

8.2K

The histone proteins in the nucleosomes are post-translationally modified (PTM) to increase or decrease access to DNA. The commonly observed PTMs are methylation, acetylation, phosphorylation, and ubiquitination of lysine amino acids in the histone H3 tail region. These histone modifications have specific meaning for the cell. Hence, they are called "histone code". The protein complex involved in histone modification is termed as "reader-writer" complex.
Writers
The writer...

8.2K

01:12

The Nucleosome Core Particle

901

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...

901

02:32

Histone Modification

13.2K

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...

13.2K

02:35

Chromatin Position Affects Gene Expression

23.3K

Chromatin is the massive complex of DNA and proteins packaged inside the nucleus. The complexity of chromatin folding and how it is packaged inside the nucleus greatly influences access to genetic information. Generally, the nucleus' periphery is considered transcriptionally repressive, while the cell's interior is considered a transcriptionally active area.
Topologically Associated Domains (TADs)
The 3-dimensional positioning of chromatin in the nucleus influences the...