H-ras p21変異体の3次元構造:シグナルスイッチ分子として機能できない分子基盤
U Krengel1, I Schlichting, A Scherer
1Max-Planck-Institut für medizinische Forschung Abteilung Biophysik, Heidelberg, Federal Republic of Germany.
Cell
|August 10, 1990
まとめ
H-rasオンコゲン変異体の構造分析は,特定の変異がGTP結合と水解にどのように影響するかを明らかにします. これらの発見は,腫瘍学的変異を理解し,標的治療を開発するために不可欠です.
科学分野:
- バイオケミストリー バイオケミストリー
- 分子生物学は分子生物学である.
- 構造生物学 構造生物学とは
背景:
- H-ras腫瘍遺伝子の産物p21は,細胞シグナル伝達経路の重要な調節体である.
- H-rasの変異は,様々なヒトがんで頻繁に発見され,制御不能の細胞増殖につながります.
- H-ras変異の構造的基礎を理解することは,標的がん治療の開発に不可欠です.
研究 の 目的:
- 5つのH-ras p21変異体のX線構造を決定するために.
- これらの変異がGTP結合と水解に影響を与える構造的メカニズムを解明する.
- GTPとGTPアゼ活性化タンパク質 (GAP) との相互作用に対する突然変異の影響を調査する.
主な方法:
- X線結晶学を用いて,5つのH-ras p21変異体のグアニンヌクレオチド結合ドメインの構造を決定した.
- 結晶構造の解像度は2.0から2.6 Åの範囲であった.
- 野生型と変異性p21タンパク質の比較構造分析が行われました.
主要な成果:
- Gly-12 (Gly-12----Arg,Gly-12----Val) の変異により,GTP結合および/または水解に干渉するより大きなサイドチェーンが導入されます.
- Gln-61 (Gln-61----His, Gln-61----Leu) の変異は,GTP水解に必要な形状の採用を妨げている.
- エフェクタ領域のAsp-38----Glu (D38E) 変異は,GAPを結合する能力を維持し,シグナリング機能が保存されていることを示しています.
結論:
- 細胞と突然変異のp21タンパク質の構造的な違いは微妙で,主にループL4とガンマリン酸周辺に影響します.
- Gly-12とGln-61の変異は,H-ras p21の固有のGTPase活性に直接影響を及ぼします.
- D38E変異は,H-ras p21の機能とGAPの相互作用における異なる領域の異なる役割を強調しています.
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