Lytic water dynamics reveal evolutionarily conserved mechanisms of ATP hydrolysis by TIP49 AAA+ ATPases.
Lytic water dynamics reveal evolutionarily conserved mechanisms of ATP hydrolysis by TIP49 AAA+ ATPases.
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DOI：
10.1016/j.str.2014.02.002
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发表时间：
2014-04-08
期刊：
影响因子：
--
通讯作者：
Werner F
中科院分区：
文献类型：
--
作者：
Afanasyeva A;Hirtreiter A;Schreiber A;Grohmann D;Pobegalov G;McKay AR;Tsaneva I;Petukhov M;Käs E;Grigoriev M;Werner F
真核TIP49a（Pontin）和TIP49b（Reptin）AAA+ ATP酶在关键细胞过程中起重要作用。由于TIP49a和TIP49b蛋白及其同源和异源寡聚体组装的不同性质，它们的弱ATP酶活性如何有助于它们的重要功能仍然在很大程度上是未知的，并且难以分析。为了规避这些复杂性，我们分析了在古菌Methanopyrus kandleri（mkTIP49）中发现的单一古老TIP49直系同源物。全原子同源性建模和分子动力学模拟验证生化检测揭示高度保守的组织原则，并确定ATP水解的关键残基。步行者B和传感器I基序之间的意外串扰影响水分子的动力学，并突出了反式作用的ATP在溶解水活化步骤中的关键作用，这对于ATP水解的缔合机制至关重要。我们研究了来自古菌M. kandleri的单一TIP49直向同源物（mkTIP49）。我们提出了一个用于ATP水解的预过渡态组装的模型。结合联合收割机计算和生化分析，揭示保守的组织原则和残基的ATP水解的AAA+ ATP酶TIP49直系同源物从古菌。他们强调了反式腺苷酸在ATP水解所必需的溶解水活化步骤中的作用。
Eukaryotic TIP49a (Pontin) and TIP49b (Reptin) AAA+ ATPases play essential roles in key cellular processes. How their weak ATPase activity contributes to their important functions remains largely unknown and difficult to analyze because of the divergent properties of TIP49a and TIP49b proteins and of their homo- and hetero-oligomeric assemblies. To circumvent these complexities, we have analyzed the single ancient TIP49 ortholog found in the archaeon Methanopyrus kandleri (mkTIP49). All-atom homology modeling and molecular dynamics simulations validated by biochemical assays reveal highly conserved organizational principles and identify key residues for ATP hydrolysis. An unanticipated crosstalk between Walker B and Sensor I motifs impacts the dynamics of water molecules and highlights a critical role of trans-acting aspartates in the lytic water activation step that is essential for the associative mechanism of ATP hydrolysis. We have studied the single TIP49 ortholog (mkTIP49) from the archaeon M. kandleri We propose a model for assembly of the pre-transition state for ATP hydrolysis Trans-aspartates downregulate ATP hydrolysis by mkTIP49 hexamers Mutational analysis confirms a highly conserved mechanism for lytic water activation Afanasyeva et al. combine computational and biochemical analysis to reveal conserved organizational principles and residues critical for ATP hydrolysis in the AAA+ ATPase TIP49 ortholog from archaea. They highlight a role of trans-aspartates in the lytic water activation step essential for ATP hydrolysis.
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DOI：
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