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首页> 外文期刊>Journal of the American Chemical Society >Transport-Relevant Protein Conformational Dynamics and Water Dynamics on Multiple Time Scales in an Archetypal Proton Channel: Insights from Solid-State NMR
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Transport-Relevant Protein Conformational Dynamics and Water Dynamics on Multiple Time Scales in an Archetypal Proton Channel: Insights from Solid-State NMR

机译：原型质子通道中多个时间尺度上与运输相关的蛋白质构象动力学和水动力学：固态NMR的见解

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摘要

The influenza M2 protein forms a tetrameric proton channel that conducts protons from the acidic endosome into the virion by shuttling protons between water and a transmembrane histidine. Previous NMR studies have shown that this histidine protonates and deprotonates on the microsecond time scale. However, M2’s proton conduction rate is 10–1000 s~(–1), more than 2 orders of magnitude slower than the histidine-water proton-exchange rate. M2 is also known to be conformationally plastic. To address the disparity between the functional time scale and the time scales of protein conformational dynamics and water dynamics, we have now investigated a W41F mutant of the M2 transmembrane domain using solid-state NMR. ~(13)C chemical shifts of the membrane-bound peptide indicate the presence of two distinct tetramer conformations, whose concentrations depend exclusively on pH and hence the charge-state distribution of the tetramers. High-temperature 2D correlation spectra indicate that these two conformations interconvert at a rate of ∼400 s~(–1) when the +2 and +3 charge states dominate, which gives the first experimental evidence of protein conformational motion on the transport time scale. Protein ~(13)C-detected water ~(1)H T_(2) relaxation measurements show that channel water relaxes an order of magnitude faster than bulk water and membrane-associated water, indicating that channel water undergoes nanosecond motion in a pH-independent fashion. These results connect motions on three time scales to explain M2’s proton-conduction mechanism: picosecond-to-nanosecond motions of water molecules facilitate proton Grotthuss hopping, microsecond motions of the histidine side chain allow water–histidine proton transfer, while millisecond motions of the entire four-helix bundle constitute the rate-limiting step, dictating the number of protons released into the virion.
机译：流感M2蛋白形成四聚体质子通道，该质子通道通过使质子在水和跨膜组氨酸之间穿梭而将质子从酸性内体导入病毒体。先前的NMR研究表明，该组氨酸在微秒级上质子化和去质子化。但是，M2的质子传导速率为10–1000 s〜（–1），比组氨酸-水质子交换速率慢2个数量级。还已知M2是构象可塑性的。为了解决功能时间尺度与蛋白质构象动力学和水动力学时间尺度之间的差异，我们现在使用固态NMR研究了M2跨膜结构域的W41F突变体。膜结合肽的〜（13）C化学位移表明存在两个不同的四聚体构象，其浓度仅取决于pH值，因此取决于四聚体的电荷态分布。高温二维相关光谱表明，当+2和+3电荷状态占优势时，这两个构象以〜400 s〜（–1）的速率互变，这为蛋白构象运动在转运时间尺度上提供了第一个实验证据。蛋白质〜（13）C检测到的水〜（1）H T_（2）弛豫度测量结果表明，相比于散装水和与膜相关的水，渠道水的弛豫速度快一个数量级，这表明渠道水在pH-下经历纳秒运动。独立的时尚。这些结果将三个时标上的运动联系起来，从而解释了M2的质子传导机制：水分子的皮秒至纳秒运动促进质子Grotthuss跳跃，组氨酸侧链的微秒运动允许水-组氨酸质子转移，而整个分子的毫秒运动四螺旋束构成了限速步骤，决定了释放到病毒体中的质子数。

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  • 来源
    《Journal of the American Chemical Society》 |2018年第4期|1514-1524|共11页
  • 作者

    Venkata S. Mandala; Martin D. Gelenter; Mei Hong;

  • 作者单位

    Department of Chemistry, Massachusetts Institute of Technology, 170 Albany Street, Cambridge, Massachusetts 02139, United States;

    Department of Chemistry, Massachusetts Institute of Technology, 170 Albany Street, Cambridge, Massachusetts 02139, United States;

    Department of Chemistry, Massachusetts Institute of Technology, 170 Albany Street, Cambridge, Massachusetts 02139, United States;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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