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A pH-Dependent Conformational Ensemble Mediates Proton Transport through the Influenza A/M2 Protein

机译：pH依赖性构象集合体介导通过A / M2流感蛋白的质子运输。

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摘要

ABSTRACT: The influenza A/M2 protein exhibits inwardly rectifying, pH-activated proton transport thatnsaturates at low pH. A comparison of high-resolution structures of the transmembrane domain at high andnlow pH suggests that pH-dependent conformational changes may facilitate proton conduction by alternatelynchanging the accessibility of theN-terminal and C-terminal regions of the channel as a proton transits throughnthe transmembrane domain.Here, we show thatM2 functionally reconstituted in liposomes populates at leastnthree different conformational states over a physiologically relevant pH range, with transition midpoints thatnare consistent with previously reported His37 pKa values.We then develop and test two similar, quantitativenmechanistic models of proton transport, where protonation shifts the equilibrium between structural statesnhaving different proton affinities and solvent accessibilities. The models account well for a collection ofnexperimental data sets over a wide range of pH values and voltages and require only a small number ofnadjustable parameters to accurately describe the data. While the kinetic models do not require any specificnconformation for the protein, they nevertheless are consistent with a large body of structural informationnbased on high-resolution nuclear magnetic resonance and crystallographic structures, optical spectroscopy,nand molecular dynamics calculations.
机译：摘要：A / M2流感病毒蛋白具有向内整流，pH激活的质子转运，该转运在低pH时会饱和。高和低pH下跨膜结构域高分辨率结构的比较表明，当质子穿过跨膜结构域时，pH依赖性构象变化可通过交替改变通道N端和C端区域的可及性来促进质子传导。在这里，我们显示在脂质体中功能性重构的M2在生理相关的pH范围内至少构成三种构象状态，其过渡中点与先前报道的His37 pKa值一致，然后我们开发并测试了两个相似的定量质子转运的定量力学模型，其中质子化在质子亲和力和溶剂可及性不同的结构状态之间移动平衡。这些模型很好地说明了在广泛的pH值和电压范围内收集的实验数据集，并且仅需要少量的可调参数即可准确地描述数据。虽然动力学模型不需要蛋白质的任何特定构象，但它们仍与基于高分辨率核磁共振和晶体学结构，光谱学和分子动力学计算的大量结构信息相一致。

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  • 来源
    《Biochemistry》 |2010年第47期|p.10061-10071|共11页
  • 作者

    Alexei L. Polishchuk James D. Lear Chunlong Ma Robert A. Lamb Lawrence H. Pinto and William F. DeGrado;

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    ‡Department of Biochemistry and Biophysics, School ofMedicine,University of Pennsylvania, Philadelphia, Pennsylvania 19104-6059,United States,§Department of Neurobiology and Physiology, and ) Department of Biochemistry,Molecular Biology and Cell Biologyand Howard Hughes Medical Institute, Northwestern University, Evanston, Illinois 60208-3500, United States;

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