电离网络在含有信号蛋白SHP2和SRC的SH2域中调解pH依赖的质
Papa Kobina Van Dyck1,2, Luke Piszkin1, Elijah A Gorski1,2
1Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556, USA.
Science signaling
|November 11, 2025
概括
细胞内pH动力学以全质调节SHP2和SRC等关键信号蛋白质. 这种依赖pH的控制与酸化一起起作用,影响细胞生物学.
科学领域:
- 细胞生物学 细胞生物学
- 生物化学 生物化学
- 计算生物学 计算生物学
背景情况:
- 细胞内pH值是细胞过程的关键调节者.
- 信号蛋白,如SHP2酸酶和SRC激酶,在细胞信号通路中起着至关重要的作用.
- 了解pH取决于蛋白质调节的机制至关重要.
研究的目的:
- 开发一个用于识别pH敏感蛋白的计算管道.
- 研究SHP2和SRC的pH依赖调节背后的分子机制.
- 探索pH敏感和酸化依赖信号之间的相互作用.
主要方法:
- 开发一个用于识别pH敏感蛋白的计算管道.
- 在体外和细胞内测试以评估不同pH值的蛋白质活性.
- 位点定向突变发生,以识别涉及pH敏感度的关键氨基酸残留物.
- 恒定pH的分子动力学模拟.
- 对pH感应网络进化保存的分析.
主要成果:
- 发现SHP2酸酶和SRC激酶活动在体外和细胞内都对pH敏感.
- 在SHP2 (His116,Glu252) 和SRC中的特定突变取消了pH敏感活性.
- 即使在EGF或相基因突变的存在下,SRC激酶活性仍然对pH敏感.
- 分子动力学模拟支持通过pH依赖的SH2域相互作用进行全调节.
- 在其他含有SH2域的蛋白质中发现了进化保守的pH感应网络.
结论:
- 细胞内pH动态在全调节SH2信号蛋白中起着重要作用.
- 依赖pH的调节补充了已建立的依赖酸化的机制.
- 这项研究揭示了由细胞内pH控制的细胞信号通路中的新型调节层.
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