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全华人研究组《Cell》上发表离子通道文章

来源:生物通 2006-10-08 08:54

        离子通道是细胞生物学研究的一个热点。2003年的诺贝尔生理/医学奖就颁发给了离子通道蛋白的发现者。MthK(钙离子活化型钾离子通道)是一种原核细胞的Ca2+门控钾离子通道,与其他的配基门控通道一样,MthK能够将与之结合的配基的化学能量转化成通道开启的机械力。          

        这种通道的8个配基结合区域(RCK结构域)形成一种八聚合体门控环。在这个环中,钙离子的结合能够诱导构型变化,从而开启通道。在最新一期的Cell杂志上,来自得克萨斯州大学西南医学中心的一个全华人研究组给出了MthK门控环的晶体结构,其分辨率达2.8埃,并且在没有钙离子的情况下获得了同样的晶体。这个研究组的负责人是蒋佑兴(Youxing  Jiang),文章的作者还包括叶胜(Sheng  Ye)、李洋(Yang  Li)和陈丽萍(Liping  Chen)。

        研究组进一步的生化和电生理分析结果证实MthK通道是通过钙离子和pH来进行控制的。钙离子通过改变门控环的关闭和开启平衡来调节该通道,而pH则通过硬性门控环的稳定性来调节通道。

        研究人员表示,这些新发现连同之前确定出的开启状态的MthK结构信息使他们得以阐明RCK调节的钾离子通道的配基门控机制。

部分英文原文:

Structures of the MthK RCK Domain and the Effect of Ca2+ on Gating Ring Stability*

From the Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390 and the Department of Molecular Medicine, Cornell University, Ithaca, New York 14853

MthK is a Ca2+-gated K+ channel from Methanobacterium autotrophicum. The crystal structure of the MthK channel in a Ca2+-bound open state was previously determined at 3.3 Å and revealed an octameric gating ring composed of eight intracellular ligand-binding RCK (regulate the conductance of K+) domains. It was suggested that Ca2+ binding regulates the gating ring conformation, which in turn leads to the opening and closing of the channel. However, at 3.3 AÅ resolution, the molecular details of the structure are not well defined, and many of the conclusions drawn from that structure were hypothetical. Here we have presented high resolution structures of the MthK RCK domain with and without Ca2+ bound from three different crystals. These structures revealed a dimeric architecture of the RCK domain and allowed us to visualize the Ca2+ binding and protein-protein contacts at atomic detail. The dimerization of RCK domains is also conserved in other RCK-regulated K+ channels and transporters, suggesting that the RCK dimer serves as a basic unit in the gating ring assembly. A comparison of these dimer structures confirmed that the dimer interface is indeed flexible as suggested previously. However, the conformational change at the flexible interface is of an extent smaller than the previously hypothesized gating ring movement, and a reconstruction of these dimers into octamers by applying protein-protein contacts at the fixed interface did not generate enclosed gating rings. This indicated that there is a high probability that the previously defined fixed interface may not be fixed during channel gating. In addition to the structural studies, we have also carried out biochemical analyses and have shown that near physiological pH, isolated RCK domains form a stable octamer in solution, supporting the notion that the formation of octameric gating ring is a functionally relevant event in MthK gating. Additionally, our stability studies indicated that Ca2+ binding stabilizes the RCK domains in this octameric state.

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