Mechanisms of isoform-specific residue influence on GTP-bound HRas, KRas, and NRas
Mechanisms of isoform-specific residue influence on GTP-bound HRas, KRas, and NRas
复制标题
异构体特异性残基对 GTP 结合 HRas、KRas 和 NRas 影响的机制
DOI：
10.1016/j.bpj.2022.07.005
复制
发表时间：
2022
影响因子：
3.4
通讯作者：
Mattos, Carla
中科院分区：
文献类型：
--
作者：
Volmar, Alicia Y.;Guterres, Hugo;Zhou, Hao;Reid, Derion;Pavlopoulos, Spiro;Makowski, Lee;Mattos, Carla
HRas、KRas和NRas是具有一组共同效应物的GTP酶，其控制许多细胞信号传导途径，包括通过Raf激酶的增殖。它们的G-结构域在序列上几乎相同，具有对动力学和生物化学性质有影响的一些同种型特异性残基。在这里，我们使用加速分子动力学（aMD）模拟与解决方案的X-射线散射实验相一致，以阐明机制，通过该机制与每个Ras亚型相关的亚型特异性残基影响连接到活性位点的功能重要的区域。HRas特异性残基聚集在环8中以稳定核苷酸结合口袋，而螺旋3上的NRas特异性残基直接影响开关I和开关II的构象。KRas是最具全局灵活性的同种型，在由环7中的KRas特异性残基和高度动态的环8区域增强的开关区域中显示出最大的波动。异构体特异性残基对Ras蛋白的影响的分析得到NMR实验的支持，并且与先前发表的生化数据一致。
HRas, KRas, and NRas are GTPases with a common set of effectors that control many cell-signaling pathways, including proliferation through Raf kinase. Their G-domains are nearly identical in sequence, with a few isoform-specific residues that have an effect on dynamics and biochemical properties. Here, we use accelerated molecular dynamics (aMD) simulations consistent with solution x-ray scattering experiments to elucidate mechanisms through which isoform-specific residues associated with each Ras isoform affects functionally important regions connected to the active site. HRas-specific residues cluster in loop 8 to stabilize the nucleotide-binding pocket, while NRas-specific residues on helix 3 directly affect the conformations of switch I and switch II. KRas, the most globally flexible of the isoforms, shows greatest fluctuations in the switch regions enhanced by a KRas-specific residue in loop 7 and a highly dynamic loop 8 region. The analysis of isoform-specific residue effects on Ras proteins is supported by NMR experiments and is consistent with previously published biochemical data.