Large-Scale Conformational Flexibility Determines the Properties of AAA+TIP49 ATPases
Large-Scale Conformational Flexibility Determines the Properties of AAA+TIP49 ATPases
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DOI：
10.1016/j.str.2012.05.012
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发表时间：
2012-08-08
期刊：
影响因子：
5.7
通讯作者：
Grigoriev, Mikhail
中科院分区：
文献类型：
--
作者：
Petukhov, Michael;Dagkessamanskaja, Adilia;Grigoriev, Mikhail
TIP 49 a和TIP 49 b蛋白属于AAA+ ATP酶家族，在转录、DNA修复、snoRNP生物发生和染色质重塑等重要过程中发挥重要作用。我们报告了TIP 49 b六聚体的晶体结构，并在水环境中使用分子模拟和分子动力学模拟对TIP 49 a，TIP 49 b和TIP 49 a/TIP 49 b复合物的大规模构象灵活性进行了比较分析。我们的研究结果建立了影响蛋白质构象和生化特性的结构域迁移率的关键原则，包括蛋白质六聚化后ATP酶活性下调的机制基础。这些方法，适用于像TIP 49 b突变体报告具有增强的DNA-独立的ATP酶活性，有助于解释如何远程三个氨基酸的插入影响ATP结合和水解口袋的结构和构象动力学，同时解偶联ATP水解从DNA结合。这可能类似于TIP 49异六聚体所采用的构象的影响。
The TIP49a and TIP49b proteins belong to the family of AAA+ ATPases and play essential roles in vital processes such as transcription, DNA repair, snoRNP biogenesis, and chromatin remodeling. We report the crystal structure of a TIP49b hexamer and the comparative analysis of large-scale conformational flexibility of TIP49a, TIP49b, and TIP49a/TIP49b complexes using molecular modeling and molecular dynamics simulations in a water environment. Our results establish key principles of domain mobility that affect protein conformation and biochemical properties, including a mechanistic basis for the downregulation of ATPase activity upon protein hexamerization. These approaches, applied to the lik-TIP49b mutant reported to possess enhanced DNA-independent ATPase activity, help explain how a three-amino acid insertion remotely affects the structure and conformational dynamics of the ATP binding and hydrolysis pocket while uncoupling ATP hydrolysis from DNA binding. This might be similar to the effects of conformations adopted by TIP49 heterohexamers.