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Structural basis for the coupling between activation and inactivation gates in K~+ channels

机译：K〜+通道中激活和失活门之间耦合的结构基础

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摘要

The coupled interplay between activation and inactivation gating is a functional hallmark of K~+ channels. This coupling has been experimentally demonstrated through ion interaction effects and cysteine accessibility, and is associated with a well defined boundary of energetically coupled residues. The structure of the K~+ channel KcsA in its fully open conformation, in addition to four other partial channel openings, richly illustrates the structural basis of activation-inactivation gating. Here, we identify the mechanistic principles by which movements on the inner bundle gate trigger conformational changes at the selectivity filter, leading to the non-conductive C-type inactivated state. Analysis of a series of KcsA open structures suggests that, as a consequence of the hinge-bending and rotation of the TM2 helix, the aromatic ring of Phe 103 tilts towards residues Thr 74 and Thr 75 in the pore-helix and towards Ile 100 in the neighbouring subunit. This allows the network of hydrogen bonds among residues Trp 67, Glu 71 and Asp 80 to destabilize the selectivity filter, allowing entry to its non-conductive conformation. Mutations at position 103 have a size-dependent effect on gating kinetics: small side-chain substitutions F103A and F103C severely impair inactivation kinetics, whereas larger side chains such as F103W have more subtle effects. This suggests that the allosteric coupling between the inner helical bundle and the selectivity filter might rely on straightforward mechanical deformation propagated through a network of steric contacts. Average interactions calculated from molecular dynamics simulations show favourable open-state interaction-energies between Phe 103 and the surrounding residues. We probed similar interactions in the Shaker K~+ channel where inactivation was impaired in the mutant I470A. We propose that side-chain rearrangements at position 103 mechanically couple activation and inactivation in KcsA and a variety of other K~+ channels.
机译：激活和失活门控之间的耦合相互作用是K〜+通道的功能标志。通过离子相互作用效应和半胱氨酸可及性已通过实验证明了该偶联，并且与能量偶联残基的明确边界相关。除了四个其他的部分通道开口之外，处于完全开放构型的K +通道KcsA的结构也充分说明了激活-失活门控的结构基础。在这里，我们确定了机械原理，通过该原理，内束栅上的运动会触发选择性过滤器的构象变化，从而导致非导电C型失活状态。对一系列KcsA开放结构的分析表明，由于TM2螺旋的铰链弯曲和旋转的结果，Phe 103的芳香环向孔螺旋中的残基Thr 74和Thr 75倾斜，并向Ile 100中的Ile 100倾斜。相邻的子单元。这允许残基Trp 67，Glu 71和Asp 80之间的氢键网络破坏选择性过滤器的稳定性，使其进入其非导电构象。 103位的突变对门控动力学具有大小依赖性：小的侧链取代F103A和F103C严重损害了失活动力学，而较大的侧链（如F103W）则具有更微妙的作用。这表明内部螺旋束和选择性过滤器之间的变构偶联可能依赖于通过空间接触网络传播的直接机械变形。由分子动力学模拟计算出的平均相互作用表明，Phe 103与周围残基之间具有良好的开放态相互作用能。我们在Shaker K +通道中探究了类似的相互作用，其中突变体I470A的失活被削弱。我们建议在位置103的侧链重排将KcsA和许多其他K +通道中的激活和失活机械耦合。

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  • 来源
    《Nature》 |2010年第7303期|P.272-275|共4页
  • 作者

    Luis G. Cuello; rnVishwanath Jogini; rnD. Marien Cortes; rnAlbert C. Pan; rnDominique G. Gagnon; rnOlivier Dalmas; Julio F. Cordero-Morales; rnSudha Chakrapani; rnBenoit Roux; rnEduardo Perozo;

  • 作者单位

    Department of Biochemistry and Molecular Biology, The University of Chicago, 929 E 57th Street, Chicago, Illinois 60637, USA Department of Cell Physiology and Molecular Biophysics, Texas Tech University, Lubbock, Texas 79430, USA;

    rnDepartment of Biochemistry and Molecular Biology, The University of Chicago, 929 E 57th Street, Chicago, Illinois 60637, USA D. E. Shaw Research, Hyderabad 500034, India;

    rnDepartment of Biochemistry and Molecular Biology, The University of Chicago, 929 E 57th Street, Chicago, Illinois 60637, USA Department of Cell Physiology and Molecular Biophysics, Texas Tech University, Lubbock, Texas 79430, USA;

    rnDepartment of Biochemistry and Molecular Biology, The University of Chicago, 929 E 57th Street, Chicago, Illinois 60637, USA D. E. Shaw Research, New York, New York 10036, USA;

    rnDepartment of Biochemistry and Molecular Biology, The University of Chicago, 929 E 57th Street, Chicago, Illinois 60637, USA;

    rnDepartment of Biochemistry and Molecular Biology, The University of Chicago, 929 E 57th Street, Chicago, Illinois 60637, USA;

    rnDepartment of Biochemistry and Molecular Biology, The University of Chicago, 929 E 57th Street, Chicago, Illinois 60637, USA;

    rnDepartment of Biochemistry and Molecular Biology, The University of Chicago, 929 E 57th Street, Chicago, Illinois 60637, USA;

    rnDepartment of Biochemistry and Molecular Biology, The University of Chicago, 929 E 57th Street, Chicago, Illinois 60637, USA Institute for Biophysical Dynamics, The University of Chicago, 929 E 57th Street, Chicago, Illinois 60637, USA;

    rnDepartment of Biochemistry and Molecular Biology, The University of Chicago, 929 E 57th Street, Chicago, Illinois 60637, USA Institute for Biophysical Dynamics, The University of Chicago, 929 E 57th Street, Chicago, Illinois 60637, USA;

  • 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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