Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2.
Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2.
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DOI：
10.1038/nature10370
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发表时间：
2011-08-28
期刊：
影响因子：
64.8
通讯作者：
MacKinnon, Roderick
中科院分区：
文献类型：
--
作者：
Hansen, Scott B.;Tao, Xiao;MacKinnon, Roderick
特定的脂质分子对离子通道活性的调节被广泛认为是细胞内电信号的一个组成部分。特别是，磷脂酰肌醇4，5-二磷酸(PIP2)是细胞膜上一种微小但动态的磷脂成分，已知可调节许多不同的离子通道。PIP2是经典的内向整流(Kir2)通道的主要激动剂，这种脂质可以通过它来调节细胞的静息膜电位。然而，PIP2发挥作用的分子机制尚不清楚。在这里，我们给出了一个含有PIP2的短链(二辛酰基)衍生物的Kir2.2沟道配合物的X射线晶体结构。我们发现PIP2结合在跨膜结构域(TMD)和细胞质结构域(CTD)之间的界面上。PIP2结合位点由TMD中保守的非特异性磷脂结合区(RWR)和CTD中的特异性磷脂酰肌醇结合区组成。当PIP2结合时，柔性扩展连接体收缩为紧凑的螺旋结构，CTD平移6？并被拴在TMD上，内螺旋门开始打开。相反，小阴离子脂质二辛酰甘油焦磷脂酸(PPA)也结合到非特异性TMD区域，但不结合特异性磷脂酰肌醇区域，因此无法与CTD结合或打开通道。我们的结果表明，PIP2是如何通过特定的离子通道受体-配体相互作用来控制静息膜电位的，这种作用带来了很大的构象变化，类似于突触离子通道的神经递质激活。
The regulation of ion channel activity by specific lipid molecules is widely recognized as an integral component of electrical signaling in cells. In particular, phosphatidylinositol 4,5-bisphosphate (PIP2), a minor yet dynamic phospholipid component of cell membranes, is known to regulate many different ion channels. PIP2 is the primary agonist for classical inward rectifier (Kir2) channels, through which this lipid can regulate a cell’s resting membrane potential. However, the molecular mechanism by which PIP2 exerts its action is unknown. Here we present the x-ray crystal structure of a Kir2.2 channel in complex with a short-chain (dioctanoyl) derivative of PIP2. We found that PIP2 binds at an interface between the transmembrane domain (TMD) and the cytoplasmic domain (CTD). The PIP2 binding site consists of a conserved non-specific phospholipid binding region (RWR) in the TMD and a specific phosphatidylinositol binding region in the CTD. Upon PIP2 binding a flexible expansion linker contracts to a compact helical structure, the CTD translates 6 Å and becomes tethered to the TMD, and the inner helix gate begins to open. In contrast, the small anionic lipid dioctanoyl glycerol pyrophosphatidic acid (PPA) also binds to the non-specific TMD region, but not to the specific phosphatidylinositol region, and thus fails to engage the CTD or open the channel. Our results show how PIP2 can control the resting membrane potential through a specific ion channel receptor-ligand interaction that brings about a large conformational change, analogous to neurotransmitter activation of ion channels at synapses.
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影响因子：
5.5
作者：
Fujiwara, Yuichiro;Kubo, Yoshihiro
通讯作者：
Kubo, Yoshihiro
影响因子：
25
作者：
Pegan, S;Arrabit, C;Choe, S
通讯作者：
Choe, S
影响因子：
7.5
作者：
Monserrate, Jessica P.;York, John D.
通讯作者：
York, John D.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
5.5
作者：
Dart, Caroline
通讯作者：
Dart, Caroline