Mechanism of bacterial signal transduction revealed by molecular dynamics of Tsr dimers and trimers of dimers in lipid vesicles.
Mechanism of bacterial signal transduction revealed by molecular dynamics of Tsr dimers and trimers of dimers in lipid vesicles.
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DOI：
10.1371/journal.pcbi.1002685
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发表时间：
2012
影响因子：
4.3
通讯作者：
Sansom MS
中科院分区：
文献类型：
--
作者：
Hall BA;Armitage JP;Sansom MS
细菌化学感受器为理解信号传导过程提供了一个重要的模型。在大肠杆菌的丝氨酸受体Tsr中，受体二聚体周围质域的结合事件导致单个跨膜螺旋向细胞质移动约0.15 nm。这种微小的变化通过受体的~ 22 nm长度传播，引起CheA激酶的下游抑制。这需要受体二聚体三聚体之间的相互作用。此外，信号在53,000 nm2的化学受体蛋白阵列中被放大，包括在细胞极点的约5,200个受体三聚体。尽管有大量关于该系统的实验数据，包括单个结构域的高分辨率结构和广泛的诱变数据，但仍然不确定信息如何通过受体从结合事件传递到下游效应器。我们提出了整个Tsr二聚体的分子模型，并使用粗粒度分子动力学和弹性网络建模来检查其行为。我们观察到在二聚体模型中，在连接域和线圈域之间存在较大的弯曲，这得到了实验数据的支持。二聚体的三聚体模型，建立在二聚体模型，更受约束，并可能代表信号状态。在70 nm直径的囊泡中模拟具有生物真实的脂质混合物的模型，揭示了特定的脂质相互作用和二聚体的三聚体的寡聚化。结果表明了一种机制，单螺旋的小运动可以通过HAMP结构域包装放大，从而引发整个受体结构的大变化。为了理解细胞信号事件，需要一个有关信号蛋白的结构和行为的物理模型。接受甲基化的化学受体蛋白引导细菌向食物来源移动，远离毒素。基于实验数据，我们建立了丝氨酸化学受体（Tsr）作为不能激活下游CheA激酶的二聚体和作为可以激活CheA的二聚体的三聚体的结构模型。我们进行了分子动力学模拟，以揭示这两种形式在平面脂质双分子层和70 nm直径的脂质囊泡中的行为，脂质混合物模拟大肠杆菌的内膜。我们表明，在隔离二聚体经历弯曲运动围绕中央HAMP结构域，而三聚体模型没有。与已发表的实验数据的比较表明，这些弯曲运动是真实的，并且它们仅在配体结合时发生在二聚体的三聚体中。将这些观察结果与表明信号事件涉及跨膜螺旋中的小活塞运动的研究结合起来，表明弯曲运动在二聚体的非配体三聚体中受到挫折，并且配体结合通过重新包装HAMP界面引起弯曲。
Bacterial chemoreceptors provide an important model for understanding signalling processes. In the serine receptor Tsr from E. coli, a binding event in the periplasmic domain of the receptor dimer causes a shift in a single transmembrane helix of roughly 0.15 nm towards the cytoplasm. This small change is propagated through the ∼22 nm length of the receptor, causing downstream inhibition of the kinase CheA. This requires interactions within a trimer of receptor dimers. Additionally, the signal is amplified across a 53,000 nm2 array of chemoreceptor proteins, including ∼5,200 receptor trimers-of-dimers, at the cell pole. Despite a wealth of experimental data on the system, including high resolution structures of individual domains and extensive mutagenesis data, it remains uncertain how information is communicated across the receptor from the binding event to the downstream effectors. We present a molecular model of the entire Tsr dimer, and examine its behaviour using coarse-grained molecular dynamics and elastic network modelling. We observe a large bending in dimer models between the linker domain HAMP and coiled-coil domains, which is supported by experimental data. Models of the trimer of dimers, built from the dimer models, are more constrained and likely represent the signalling state. Simulations of the models in a 70 nm diameter vesicle with a biologically realistic lipid mixture reveal specific lipid interactions and oligomerisation of the trimer of dimers. The results indicate a mechanism whereby small motions of a single helix can be amplified through HAMP domain packing, to initiate large changes in the whole receptor structure. To understand cell signalling events requires a physical model of the structure and behaviour of the signalling proteins involved. The methyl-accepting chemoreceptor proteins direct bacterial movement towards food sources and away from toxins. Based on experimental data we have built structural models of the serine chemoreceptor (Tsr) as a dimer, which is incapable of activating the downstream kinase CheA, and as a trimer of dimers, which can activate CheA. We have performed molecular dynamics simulation to reveal the behaviour of these two forms in a planar lipid bilayer and in a 70 nm diameter lipid vesicle with a mixture of lipids mimicking the E. coli inner membrane. We show that in isolation the dimers undergo a bending movement around the central HAMP domain, whereas the trimer-of-dimers model does not. Comparison with published experimental data suggests that these bending motions are real, and that they occur in the trimer of dimers only in response to ligand binding. Drawing together these observations with studies showing that the signalling event involves small piston motions in the transmembrane helices suggests that the bending motion is frustrated in the unliganded trimer of dimers, and that ligand binding induces bending by repacking the HAMP interface.
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影响因子：
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