Gating machinery of InsP3R channels revealed by electron cryomicroscopy.
Gating machinery of InsP3R channels revealed by electron cryomicroscopy.
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DOI：
10.1038/nature15249
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发表时间：
2015-11-19
期刊：
影响因子：
64.8
通讯作者：
Serysheva II
中科院分区：
文献类型：
--
作者：
Fan G;Baker ML;Wang Z;Baker MR;Sinyagovskiy PA;Chiu W;Ludtke SJ;Serysheva II
肌醇-1，4，5-三磷酸受体（InsP 3Rs）是负责细胞溶质Ca 2+信号传导的普遍存在的离子通道，并且对于从收缩到分泌以及从增殖到细胞死亡的广泛的细胞过程是必需的。尽管对InsP 3R进行了数十年的研究，但缺乏对其结构-功能关系的机制理解。在这里，我们提出了第一个，据我们所知，近原子（4.7 μ m）分辨率的电子冷冻显微镜结构的四聚体哺乳动物1型InsP 3R通道在其apo-state。在这个分辨率下，我们能够明确地追踪~85%的蛋白质骨架，使我们能够识别参与门控和调节这个1.3兆道尔顿通道的结构元件。虽然中央Ca 2+传导途径与其他离子通道（包括密切相关的ryanodine受体）相似，但胞质羧基末端独特地排列在左手α螺旋束中，直接与相邻亚基的氨基末端结构域相互作用。这种结构表明细胞内信号对通道门控进行变构调节的分子机制。
Inositol-1,4,5-trisphosphate receptors (InsP3Rs) are ubiquitous ion channels responsible for cytosolic Ca2+ signalling and essential for a broad array of cellular processes ranging from contraction to secretion, and from proliferation to cell death. Despite decades of research on InsP3Rs, a mechanistic understanding of their structure–function relationship is lacking. Here we present the first, to our knowledge, near-atomic (4.7 Å) resolution electron cryomicroscopy structure of the tetrameric mammalian type 1 InsP3R channel in its apo-state. At this resolution, we are able to trace unambiguously ~85% of the protein backbone, allowing us to identify the structural elements involved in gating and modulation of this 1.3-megadalton channel. Although the central Ca2+-conduction pathway is similar to other ion channels, including the closely related ryanodine receptor, the cytosolic carboxy termini are uniquely arranged in a left-handed α-helical bundle, directly interacting with the amino-terminal domains of adjacent subunits. This configuration suggests a molecular mechanism for allosteric regulation of channel gating by intracellular signals.