A water-mediated allosteric network governs activation of Aurora kinase A
A water-mediated allosteric network governs activation of Aurora kinase A
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DOI：
10.1038/nchembio.2296
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发表时间：
2017-04-01
影响因子：
14.8
通讯作者：
Levinson, Nicholas M.
中科院分区：
文献类型：
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作者：
Cyphers, Soreen;Ruff, Emily F.;Levinson, Nicholas M.
许多蛋白激酶的催化活性是由保守的Asp-Phe-Gly（DFG）基序的构象变化控制的。我们使用红外探针跟踪有丝分裂激酶Aurora A（AurA）的DFG基序，发现纺锤体相关蛋白Tpx 2的变构激活涉及向活性DFG-in状态的平衡转变。福斯特共振能量转移实验表明，激活环经历了纳米尺度的运动，是紧密耦合的DFG平衡。Tpx 2通过稳定水介导的变构网络进一步激活AurA，该网络通过调节脊柱中的不寻常的极性残基将C-螺旋连接到活性位点。AurA的极性脊残基和水网络对于磷酸化驱动的激活是必不可少的，但是在相关激酶中发现的水网络的替代形式可以支持Tpx 2驱动的激活，这表明水介导的氢键网络的变化介导蛋白激酶的调节多样化。
The catalytic activity of many protein kinases is controlled by conformational changes of a conserved Asp-Phe-Gly (DFG) motif. We used an infrared probe to track the DFG motif of the mitotic kinase Aurora A (AurA) and found that allosteric activation by the spindle-associated protein Tpx2 involves an equilibrium shift toward the active DFG-in state. Forster resonance energy transfer experiments show that the activation loop undergoes a nanometer-scale movement that is tightly coupled to the DFG equilibrium. Tpx2 further activates AurA by stabilizing a water-mediated allosteric network that links the C-helix to the active site through an unusual polar residue in the regulatory spine. The polar spine residue and water network of AurA are essential for phosphorylation-driven activation, but an alternative form of the water network found in related kinases can support Tpx2-driven activation, suggesting that variations in the water-mediated hydrogen bond network mediate regulatory diversification in protein kinases.