一个分子内能量网络调节了SH2域中的连接体识别
Caterina Nardella1, Livia Pagano1, Valeria Pennacchietti1
1Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza Università di Roma, Rome, Italy.
Protein science : a publication of the Protein Society
|July 19, 2023
概括
研究人员探索了SHP2蛋白质的C端SH2域如何识别连接体,找到遥远的残留物和一个关键的能量网络来结合Gab2支架蛋白.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 蛋白质与蛋白质之间的相互作用
背景情况:
- SHP2蛋白是一种关键的氨酸酸酶,参与各种信号通路.
- SH2域通过识别酸化氨酸残留物来调解蛋白质与蛋白质的相互作用.
- 了解SH2域联体识别对于破译细胞信号和疾病机制至关重要.
研究的目的:
- 调查SHP2.2的C端SH2域 (C-SH2) 调控联体识别的分子决定因素.
- 描述SHP2 C-SH2域与一个模仿Gab2之间的结合动力学和热力学.
- 确定涉及SHP2 C-SH2/Gab2相互作用的特异性和亲和性的关键残留物和网络.
主要方法:
- 在SHP2 C-SH2域的位点定向突变发生.
- 动力结合实验使用Gab2脚手架蛋白的仿真体.
- 双重突变周期分析以探测绑定接口的能量网络.
主要成果:
- 从拓学上远离正规结合口袋的残留物显著影响的识别和结合.
- 确定了一个稀疏的能量网络,调节了SHP2 C-SH2域和Gab2.2之间的相互作用.
- 在Gab2的+3位置的突变揭示了在早期和晚期结合事件中发挥关键作用.
结论:
- SHP2 C-SH2 域利用了一个广泛的,非正规的能量网络来识别连接体,超越了直接的结合口袋.
- 已识别的网络和特定的Gab2残留物有助于该域与多个细胞内合作伙伴相互作用的能力.
- 这些发现提供了关于SHP2介导信号和潜在治疗点的监管机制的见解.
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