深入了解Grp94分子伴侣的基于核酸的调制,使用多层次动力学
John Paul Alao1, Ikponwmosa Obaseki1, Yaa Sarfowah Amankwah1
1Department of Chemistry & Biochemistry, Miami University, Oxford, Ohio 45056, United States.
The journal of physical chemistry. B
|June 9, 2023
概括
在Grp94 (一个ER局部化的分子伴侣) 中的ATP水解改变了它的全电线. 这一过程增强了分子的移动性,促进了对蛋白质折叠和激活至关重要的大规模结构变化.
科学领域:
- 分子生物学分子生物学
- 生物化学 生物化学
- 结构生物学 结构生物学
背景情况:
- Grp94是一种内分泌网膜 (ER) 局部化的分子伴侣,对于折叠和激活膜和分泌蛋白质至关重要.
- Grp94的客户端激活机制涉及核酸结合和形状变化.
- 了解微观核酸水解事件与宏观Grp94形状变化之间的联系至关重要.
研究的目的:
- 阐明核酸水解中的微观变化如何驱动Grp94.4中的大规模构造变化.
- 调查不同核酸结合状态对Grp94动态和全沟通的作用.
主要方法:
- 全原子分子动力学 (MD) 在四个不同的核酸结合状态下模拟Grp94二元体.
- 正常模式分析 (NMA) 使用弹性网络模型来研究大规模的结构动力学.
- 随机扰动 (SPM) 分析,以确定涉及构造信号的关键残留物.
主要成果:
- 在ATP结合状态下,Grp94表现出最大的刚性.
- ATP水解或核酸去除增加了N端域和ATP盖的流动性,减少了域间通信.
- 一个含有水解核酸的不对称构造显示出一个紧的状态,与实验数据一致.
- 确定了一种灵活的链接器,可以通过与M域螺旋体的静电相互作用来潜在地调节Grp94活动.
- SPM分析确定了ATP协调,催化,客户端结合和BiP相互作用部位中的功能相关残留物.
结论:
- ATP 解显著改变了 Grp94.4.4 内的全网络.
- 这些变化促进了陪伴者功能所需的基本的大规模形状变化.
- 研究结果提供了关于Grp94的调控机制及其相互作用的见解.
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