Structural investigation of MscL gating using experimental data and coarse grained MD simulations.
Structural investigation of MscL gating using experimental data and coarse grained MD simulations.
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DOI：
10.1371/journal.pcbi.1002683
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发表时间：
2012
影响因子：
4.3
通讯作者：
Corry B
中科院分区：
文献类型：
--
作者：
Deplazes E;Louhivuori M;Jayatilaka D;Marrink SJ;Corry B
大电导机械敏感通道（mechanosensitive channel of large conductance，MscL）已成为研究机械感觉的模型系统，机械感觉是一个参与神经调节和许多其他生理功能的过程。虽然高分辨率的封闭状态结构是可用的，但开放结构和门控机制的细节仍然未知。在这项研究中，我们结合联合收割机粗粒度的模拟与EPR和FRET实验的限制，以研究结构的变化，涉及门控与更大程度的构象采样比以前可能的。我们产生了一组合理的开孔结构，同意与现有的开孔结构和门控模型。最有趣的是，我们发现，膜变薄诱导的扭结在TM1的上部，导致向外运动的周质环远离孔中心。这种以前未观察到的结构变化可能提出了一种新的张力感知机制，并可能与神经调节的功能作用有关。生物有机体中的细胞必须能够在诸如触觉、听觉、痛觉和组织生长等过程中对机械力做出反应。实现这一点的一种方式是通过机械敏感离子通道，膜嵌入蛋白质，其在细胞或细胞膜内的张力下启动电信号。这些通道的功能障碍也与一系列疾病有关，包括肌肉萎缩症和心律失常。在这篇手稿中，我们详细研究了机械敏感通道的大电导（MscL）从细菌，模型系统中，以了解机械感觉的原则。尽管多年的研究工作，蛋白质如何感知周围膜张力的细节仍然未知。通过将实验的结构数据与计算机模拟相结合，我们能够模拟蛋白质的开放通道结构，并报告以前未观察到的结构变化，这些变化可能会提出一种新的感知张力的机制。本文发展的方法不仅限于研究机械敏感离子通道，而且可能有助于了解其他膜蛋白的结构和功能。
The mechanosensitive channel of large conductance (MscL) has become a model system in which to understand mechanosensation, a process involved in osmoregulation and many other physiological functions. While a high resolution closed state structure is available, details of the open structure and the gating mechanism remain unknown. In this study we combine coarse grained simulations with restraints from EPR and FRET experiments to study the structural changes involved in gating with much greater level of conformational sampling than has previously been possible. We generated a set of plausible open pore structures that agree well with existing open pore structures and gating models. Most interestingly, we found that membrane thinning induces a kink in the upper part of TM1 that causes an outward motion of the periplasmic loop away from the pore centre. This previously unobserved structural change might present a new mechanism of tension sensing and might be related to a functional role in osmoregulation. Cells in biological organisms have to be able to respond to mechanical forces during processes such as touch, hearing, pain sensation and tissue growth. One way this is achieved is through mechanosensitive ion channels, membrane embedded proteins that initiate electrical signalling upon tension within the cell or cell membrane. The malfunction of such channels is also associated with a range of diseases including muscular dystrophy and cardiac arrhythmia. In this manuscript, we study in detail the mechanosensitive channel of large conductance (MscL) from bacteria, a model system in which to understand the principles of mechanosensation. Despite many years of investigative work the details of how the protein senses tension in the surrounding membrane remain unknown. By combining structural data from experiments with computer simulation we are able to model the open channel structure of the protein and report previously unobserved structural changes that might present a new mechanism of sensing tension. The methods developed in this paper are not limited to the study of mechanosensitive ion channels and may be useful in understanding the structure and function of other membrane proteins.
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影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
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影响因子：
3.4
作者：
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DOI：
10.1085/jgp.200910376
发表时间：
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期刊：
The Journal of general physiology
影响因子：
--
作者：
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通讯作者：
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作者：
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