Transmembrane helix dynamics of bacterial chemoreceptors supports a piston model of signalling.
Transmembrane helix dynamics of bacterial chemoreceptors supports a piston model of signalling.
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DOI：
10.1371/journal.pcbi.1002204
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发表时间：
2011-10
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
跨膜α-螺旋在许多受体中发挥关键作用，将信号从脂质双层膜的一侧传递到另一侧。细菌化学感受器是研究得最好的系统之一，大量的生物物理和突变数据表明TM 2螺旋在信号传导中的关键作用。特别是芳香族（Trp和Tyr）和碱性（Arg）残基有助于将α-螺旋锁定在膜中。TM 2突变株E.大肠杆菌焦油和相关的化学感受器涉及这些残基牵连的螺旋位置和/或方向的信号。我们已经调查了详细的结构基础，这通过高通量粗粒度分子动力学（CG-MD）的焦油TM 2和它的突变体在脂质双层。我们专注于TM 2相对于双层的位置（移位）和方向（倾斜，旋转），以及这些是如何在突变体中相对于野生型扰动。模拟结果显示，小（约）之间存在明显的相关性。1.5 TM 2沿着双层的位置移动和信号传导活性的下游变化。在螺旋倾斜的情况下观察到较弱的相关性，并且在信号传导和螺旋扭曲之间几乎没有相关性。这种对相对细微变化的分析之所以成为可能，是因为高通量模拟方法允许我们对大量不同螺旋序列运行大型（n=100）集合，总计约。 总共2000次模拟。总体而言，该分析支持焦油和相关化学感受器的跨膜信号传导的摆动活塞模型。理解信号在脂质双层中传递的物理机制是解释细胞信号传导的核心。我们已经使用了一种新的技术进行模拟的跨膜（TM）螺旋的相互作用，从细菌的甲基接受化学受体蛋白与脂质双层膜。这些化学感受器信号蛋白通过使细胞偏向食物来源而远离毒素来决定细菌的行为。这些蛋白质通过膜的信号传导机制仍不清楚，尽管不同组分的结构表征。研究人员已经在TM 2螺旋中产生了大量的突变体，但是由这些突变体诱导的螺旋行为的精确变化并不总是清楚的。我们的模拟方法允许突变的后果被明确地解释在TM 2螺旋的位置和方向的变化。我们的研究结果为受体焦油和Trg支持的“摆动活塞”模型的信号，在倾斜和位置的螺旋相对于双层的变化赋予信号。这种方法可以扩展到一系列的TM信号事件不同类别的受体，因此代表了TM螺旋诱变实验的解释的进步。
Transmembrane α-helices play a key role in many receptors, transmitting a signal from one side to the other of the lipid bilayer membrane. Bacterial chemoreceptors are one of the best studied such systems, with a wealth of biophysical and mutational data indicating a key role for the TM2 helix in signalling. In particular, aromatic (Trp and Tyr) and basic (Arg) residues help to lock α-helices into a membrane. Mutants in TM2 of E. coli Tar and related chemoreceptors involving these residues implicate changes in helix location and/or orientation in signalling. We have investigated the detailed structural basis of this via high throughput coarse-grained molecular dynamics (CG-MD) of Tar TM2 and its mutants in lipid bilayers. We focus on the position (shift) and orientation (tilt, rotation) of TM2 relative to the bilayer and how these are perturbed in mutants relative to the wildtype. The simulations reveal a clear correlation between small (ca. 1.5 Å) shift in position of TM2 along the bilayer normal and downstream changes in signalling activity. Weaker correlations are seen with helix tilt, and little/none between signalling and helix twist. This analysis of relatively subtle changes was only possible because the high throughput simulation method allowed us to run large (n = 100) ensembles for substantial numbers of different helix sequences, amounting to ca. 2000 simulations in total. Overall, this analysis supports a swinging-piston model of transmembrane signalling by Tar and related chemoreceptors. Understanding the physical mechanisms by which signals are transduced across a lipid bilayer is central to an account of cell signalling. We have used a novel technique for performing simulations to model the interactions of transmembrane (TM) helices from bacterial methyl accepting chemoreceptor proteins with lipid bilayer membranes. These chemoreceptor signalling proteins dictate bacterial behaviour by biasing the movement of the cell towards food sources and away from toxins. The mechanism of signalling by these proteins through the membrane remains unclear, despite structural characterization of different components. Researchers have generated a large number of mutants in the TM2 helix, but the precise changes in helical behaviour which are induced by these mutants are not always clear. Our simulation approach allows the consequences of mutations to be unambiguously interpreted in terms of changes of position and orientation of the TM2 helix. Our results for the receptors Tar and Trg support a “swinging piston” model of signalling where changes in tilt and position of the helix relative the bilayer confer signals. This approach may be extended to a range of TM signalling events different classes of receptors and thus represents an advance in the interpretation of TM helix mutagenesis experiments.
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影响因子：
2.9
作者：
Draheim, RR;Bormans, AF;Manson, MD
通讯作者：
Manson, MD
影响因子：
3.4
作者：
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作者：
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