Modulation of p53 N-terminal transactivation domain 2 conformation ensemble and kinetics by phosphorylation
Modulation of p53 N-terminal transactivation domain 2 conformation ensemble and kinetics by phosphorylation
复制标题
通过磷酸化调节 p53 N 端反式激活结构域 2 构象整体和动力学
DOI：
10.1080/07391102.2019.1637784
复制
发表时间：
2020-06
影响因子：
4.4
通讯作者：
Zhang Zhuqing
中科院分区：
文献类型：
--
作者：
Zhao Likun;Ouyang Yanhua;Li Qian;Zhang Zhuqing
摘要蛋白质的磷酸化是细胞各种过程的关键，它优先发生在内在无序蛋白质（IDP）中。磷酸化如何调节无序肽的结构系综仍然在很大程度上未被探索。本文采用复制交换分子动力学（REMD）和马尔可夫状态模型（MSM）模拟了p53 N端反式激活结构域2及其双位点磷酸化形式（pSer 46，pThr 55）的构象分布和动力学。它表明，双磷酸化不改变整体尺寸和二级结构元素分数，而氢键分布的变化诱导稍微更多的预先存在的绑定螺旋构象。MSM分析表明，双重磷酸化促进了靶结合区的无序和有序构象之间的转换。这表明磷酸化后的p53 TAD 2更容易通过不同的结合机制与人p62 pleckstrin同源（PH）结构域和酵母tfb 1 PH结构域结合，其中实验上它分别表现出延伸和α-螺旋构象，在两种复合物中的结合强度增加。我们的研究表明，除了结合界面，构象整体和动力学应该考虑磷酸化对IDPs的影响。缩写IDPs内在无序蛋白REMD复制交换分子动力学MSM马尔可夫状态模型EDP反式激活结构域PH普列克底物蛋白同源性PRR脯氨酸富集区DBD DNA结合结构域TET四聚化结构域REG调控结构域MD分子动力学PME粒子网格EwaldTICA时滞独立成分分析CK Chapman-Kolmogorov GMRQ广义矩阵Rayleigh矩阵SARW自避免随机游走KID激酶-诱导结构域MFPT平均首次通过时间DSSP蛋白质二级结构定义RMSD均方根偏差Rg回转半径Ree末端到末端距离Sarma
Abstract Phosphorylation of protein is critical for various cell processes, which preferentially happens in intrinsically disordered proteins (IDPs). How phosphorylation modulates structural ensemble of disordered peptide remains largely unexplored. Here, using replica exchange molecular dynamics (REMD) and Markov state model (MSM), the conformational distribution and kinetics of p53 N-terminal transactivation domain (TAD) 2 as well as its dual-site phosphorylated form (pSer46, pThr55) were simulated. It reveals that the dual phosphorylation does not change overall size and secondary structure element fraction, while a change in the distribution of hydrogen bonds induces slightly more pre-existing bound helical conformations. MSM analysis indicates that the dual phosphorylation accelerates conformation exchange between disordered and order-like states in target-binding region. It suggests that p53 TAD2 after phosphorylation would be more apt to bind to both the human p62 pleckstrin homology (PH) domain and the yeast tfb1 PH domain through different binding mechanism, where experimentally it exhibits an extended and α-helix conformation, respectively, with increased binding strength in both complexes. Our study implies except binding interface, both conformation ensemble and kinetics should be considered for the effects of phosphorylation on IDPs. AbbreviationsIDPs intrinsically disordered proteinsREMD replica exchange molecular dynamicsMSM Markov state modelTAD transactivation domainPH pleckstrin homologyPRR proline-rich regionDBD DNA-binding domainTET Tetramerization domainREG regulatory domainMD molecular dynamicsPME particle-mesh EwaldTICA time-lagged independent component analysisCK Chapman–KolmogorovGMRQ generalized matrix Rayleigh quotientSARW self-avoiding random walkKID kinase-inducible domainMFPT mean first passage timeDSSP definition of secondary structure of proteinsRMSD root mean square deviationRg radius of gyrationRee end to end distance Communicated by Ramaswamy H. Sarma
登录
查看更多内容
影响因子：
5.5
作者：
Schwantes, Christian R.;Pande, Vijay S.
通讯作者：
Pande, Vijay S.
影响因子：
15
作者：
Bhowmick A;Brookes DH;Yost SR;Dyson HJ;Forman-Kay JD;Gunter D;Head-Gordon M;Hura GL;Pande VS;Wemmer DE;Wright PE;Head-Gordon T
通讯作者：
Head-Gordon T
影响因子：
15
作者：
Martin EW;Holehouse AS;Grace CR;Hughes A;Pappu RV;Mittag T
通讯作者：
Mittag T
影响因子：
6.2
作者：
Okuda M;Nishimura Y
通讯作者：
Nishimura Y
DOI：
10.1073/pnas.0804608105
发表时间：
2008-11-04
影响因子：
11.1
作者：
Cai, Xin;Liu, Xuan
通讯作者：
Liu, Xuan