サブストラットと製品複合体は,HHATによるヘッジホッグアサイレーションのメカニズムを明らかにする
Yiyang Jiang1, Thomas L Benz1, Stephen B Long2
1Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Science (New York, N.Y.)
|June 11, 2021
まとめ
ヘッジホッグアシルトランスフェラーゼ (HHAT) は,シグナル伝達と癌の発生のためにヘッジホッグタンパク質を改変する. 構造的な洞察は,HHATが細胞膜内でどのように機能するかを明らかにし,新しいがん薬の開発の可能性を提供します.
科学分野:
- 生物化学
- 構造生物学
- 分子生物学
背景:
- ヘッジホッグのタンパク質は 動物の発達に不可欠であり 人間の癌に関与しています
- 翻訳後の改変,特にヘッジホッグアシルトランスフェラーゼ (HHAT) によるアミノ端パルミトイレーションは,ヘッジホッグタンパク質の機能に不可欠である.
- HHATのメカニズムを理解することは,ヘッジホッグのシグナル伝達経路と腫瘍発生におけるその役割を解読するのに不可欠です.
研究 の 目的:
- HHATによるヘッジホッグタンパク質のパルミトイレーションの構造的およびメカニズム的基礎を解明する.
- 高解像度構造の洞察をHHAT基板複合体と触媒プロセスに提供する.
- 関連アシレーション酵素とがん治療に対するこれらの発見の影響を調査する.
主な方法:
- ヒトのHATの構造を決定するために,冷凍電子顕微鏡 (cryo-EM) が使用された.
- HHATの構造は,そのパルミトイール-共酵素A基質とパルミトイール化ヘッジホッグペプチドとの複合体で得られた.
- 高解像度データ (2.7 と 3.2 アングストロム) で,詳細な原子レベルの分析が可能になった.
主要な成果:
- 人間のHHATの高解像度の冷凍-EM構造を決定し,基板との相互作用を明らかにした.
- 構造は,HHATが活性部位内で膜関連基板を結びつけることで触媒を容易にすることを示しています.
- HHATの機能を規定するメカニズム的原理が明らかにされ,基板の関与に対するユニークなアプローチが強調されました.
結論:
- 決定された構造は,HATによるヘッジホッグタンパク質のパルミトイレーションのメカニズムに前例のない洞察を提供します.
- これらの発見は,HHATが膜に埋め込まれた活性部位内に異なる性質を持つ基板を収容する際の課題を克服する方法を示しています.
- HHATの構造とメカニズムの理解は,標的がん阻害剤の開発の道を開く可能性があります.
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