核細胞結合BAF複合体の構造
Shuang He1,2, Zihan Wu1,2, Yuan Tian1,2
1Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, and Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College of Fudan University, Shanghai 200032, China.
Science (New York, N.Y.)
|February 1, 2020
まとめ
この研究は,ヒトのBRG1/BRM関連因子 (BAF) コンプレックスが核細胞に結合する構造を明らかにした. クロマチンリモデラー
科学分野:
- 分子生物学
- 構造生物学
- 生物化学
背景:
- BRG1/BRM関連因子 (BAF) とポリブローム関連BAF (PBAF) を含む哺乳類のSWI/SNF複合体は,クロマチンの構造と遺伝子転写の重要な調節因子である.
- 機能不全のSWI/SNF複合体,特にBAFは,そのサブユニットの変異により,様々なヒトがんに関与しています.
- BAF-核細胞相互作用の構造的基礎を理解することは,細胞プロセスと疾患におけるその役割を解読するために不可欠です.
研究 の 目的:
- ヒトのBAF複合体の高解像度構造を明らかにする.
- BAF複合体のサブユニット組織と核細胞認識メカニズムについての詳細な洞察を提供すること.
- BAFサブユニットとヌクレオソームの間の重要な相互作用を特定し,特に癌に関連した変異に焦点を当てます.
主な方法:
- 低温電子顕微鏡 (cryo-EM) を用いて,ヒトBAF核細胞複合体の構造を3. 7アングストームの解像度で決定した.
- BAFサブユニットと核細胞DNAおよびヒストンの間の相互作用を特徴付けるために生化学的および構造的分析が行われました.
主要な成果:
- 凍結EM構造は,核細胞がBAF複合体の塩基とアデノシントリフォスファターゼ (ATPase) モジュールの間に位置し,アクチン関連タンパク質 (ARP) モジュールによって接続されていることを示しています.
- ATPアゼモーターは核細胞DNAの近くに位置し,ATPの水解によって核細胞細胞に沿ってDNAの転位を容易にする.
- SMARCB1サブユニットのC端のヘリクスは,核細胞の酸性パッチと相互作用し,この領域はがんで頻繁に変異します.
- AT豊富なインタラクティブドメインを含むタンパク質1A (ARID1A) とSMARCCは,それぞれBAFベースモジュールの構造的コアとエスカフォルドを形成する.
結論:
- この研究は,ヒトのBAF複合体が核細胞と相互作用する前例のない構造的詳細を提供します.
- これらの発見は,BAFがクロマチンを再構成するメカニズムを明らかにし,SMARCB1のようなサブユニットにおける癌に関連した変異の構造的重要性を強調しています.
- 決定された構造は,遺伝子調節におけるBAF機能と腫瘍形成におけるその役割を理解するための基礎として機能する.
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