Structures of the excited states of phospholamban and shifts in their populations upon phosphorylation.
Structures of the excited states of phospholamban and shifts in their populations upon phosphorylation.
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DOI：
10.1021/bi400517b
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发表时间：
2013-09-24
期刊：
影响因子：
2.9
通讯作者：
Vendruscoo, Michele
中科院分区：
文献类型：
--
作者：
De Simone, Alfonso;Gustavsson, Martin;Montalvao, Rinaldo W.;Shi, Lei;Veglia, Gianluigi;Vendruscoo, Michele
受磷蛋白是一种整合膜蛋白，它控制心肌细胞中的钙平衡。由于该蛋白的功能和调节需要低丰度状态与天然状态平衡的积极参与，获取有关这些状态的结构信息就极具意义。在这项工作中，我们通过在分子动力学模拟中纳入核磁共振（NMR）残余偶极耦合（RDCs）作为副本平均结构约束，确定了受磷蛋白基态和三个主要激发态的构象及分布。然后我们描述了丝氨酸16位磷酸化通过增加其激发态的分布来调节该蛋白活性的方式。这些结果表明，我们所描述的方法对决定这种膜蛋白功能和调节的受磷蛋白不同状态进行了详细的表征。我们预计，构象集合体的可用性将为开发通过调节受磷蛋白构象亚态的相对分布来控制其活性的治疗策略提供机会。
Phospholamban is an integral membrane protein that controls the calcium balance in cardiac muscle cells. As the function and regulation of this protein require the active involvement of low populated states in equilibrium with the native state, it is of great interest to acquire structural information about them. In this work we determine the conformations and populations of the ground state and the three main excited states of phospholamban by incorporating nuclear magnetic resonance (NMR) residual dipolar couplings (RDCs) as replica-averaged structural restraints in molecular dynamics simulations. We then provide a description of the manner in which phosphorylation at Ser16 modulates the activity of the protein by increasing the populations of its excited states. These results demonstrate that approach that we describe provides a detailed characterisation of the different states of phospholamban that determine the function and regulation of this membrane protein. We anticipate that the availability of conformational ensembles will provide opportunities for the development of therapeutic strategies to control the activity of phospholamban by modulating the relative populations of its conformational substates.
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影响因子：
64.8
作者：
Bouvignies, Guillaume;Vallurupalli, Pramodh;Hansen, D. Flemming;Correia, Bruno E.;Lange, Oliver;Bah, Alaji;Vernon, Robert M.;Dahlquist, Frederick W.;Baker, David;Kay, Lewis E.
通讯作者：
Kay, Lewis E.
影响因子：
5.6
作者：
Gustavsson, Martin;Traaseth, Nathaniel J.;Veglia, Gianluigi
通讯作者：
Veglia, Gianluigi
影响因子：
56.9
作者：
FRAUENFELDER, H;SLIGAR, SG;WOLYNES, PG
通讯作者：
WOLYNES, PG
影响因子：
4.4
作者：
Cavalli, Andrea;Camilloni, Carlo;Vendruscolo, Michele
通讯作者：
Vendruscolo, Michele
影响因子：
15
作者：
Camilloni, Carlo;Robustelli, Paul;Vendruscolo, Michele
通讯作者：
Vendruscolo, Michele