Structure of full-length human TRPM4.
Structure of full-length human TRPM4.
复制标题
全长人类 TRPM4 的结构
DOI：
10.1073/pnas.1722038115
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发表时间：
2018-03-06
影响因子：
11.1
通讯作者：
Clapham DE
中科院分区：
文献类型：
--
作者：
Duan J;Li Z;Li J;Santa-Cruz A;Sanchez-Martinez S;Zhang J;Clapham DE
离子通道是介导离子穿过细胞膜的蛋白质。一种称为hTRPM 4的离子通道的人类基因突变是一种进行性家族性心脏传导阻滞的基础。然而，它在许多组织中的分布表明它的功能是广泛的。我们已经解决了hTRPM 4的原子结构，总分辨率为3.7 μ m。通道由围绕中心孔的四个相同的亚基组成。我们显示的Na+离子通过通道的路径，并指出方面的通道的内部机制，可能会影响其功能。该结构将使更多的定向实验，以了解该通道的生理功能。瞬时受体电位melastatin亚家族成员4（TRPM 4）是广泛分布的、钙激活的、单价选择性阳离子通道。人类TRPM 4（hTRPM 4）突变导致进行性家族性心脏传导阻滞。在这里，我们报告的电子低温显微镜结构的hTRPM 4在一个封闭的，Na+结合，载脂蛋白状态在pH值为7.5的总分辨率为3.7 μ m。提出五个部分水合的钠离子占据传导孔的中心和螺旋结构域的入口。我们在选择性过滤器中确定了一个上门，在细胞质卷曲螺旋结构域的入口处确定了一个下门。TRP结构域与S4-S5接头、N-末端结构域以及N和C末端之间存在分子内相互作用。最后，我们通过π-π键和阳离子-π键，在N-连接的胞外位点的糖基化，孔环二硫键和24个脂质结合位点确定了芳香族相互作用。我们比较和对比这种结构与其他TRP通道，并讨论潜在的机制，人类全长TRPM 4的调节和门控。
Significance Ion channels are proteins that mediate the flow of ions across cell membranes. Human genetic mutations of one type of ion channel, called hTRPM4, underlie a form of progressive familial heart block. Its distribution among many tissues, however, suggests that its functions are broad. We have solved the atomic structure of hTRPM4 to an overall resolution of 3.7 Å. The channel is composed of four identical subunits surrounding a central pore. We show the path of Na+ ions through the channel and point out aspects of the channel’s internal machinery that may affect its function. The structure will enable more directed experiments to understand the physiological function of this channel. Transient receptor potential melastatin subfamily member 4 (TRPM4) is a widely distributed, calcium-activated, monovalent-selective cation channel. Mutations in human TRPM4 (hTRPM4) result in progressive familial heart block. Here, we report the electron cryomicroscopy structure of hTRPM4 in a closed, Na+-bound, apo state at pH 7.5 to an overall resolution of 3.7 Å. Five partially hydrated sodium ions are proposed to occupy the center of the conduction pore and the entrance to the coiled-coil domain. We identify an upper gate in the selectivity filter and a lower gate at the entrance to the cytoplasmic coiled-coil domain. Intramolecular interactions exist between the TRP domain and the S4–S5 linker, N-terminal domain, and N and C termini. Finally, we identify aromatic interactions via π–π bonds and cation–π bonds, glycosylation at an N-linked extracellular site, a pore-loop disulfide bond, and 24 lipid binding sites. We compare and contrast this structure with other TRP channels and discuss potential mechanisms of regulation and gating of human full-length TRPM4.
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影响因子：
16.2
作者：
Aggarwal, SK;MacKinnon, R
通讯作者：
MacKinnon, R
影响因子：
30.5
作者：
通讯作者：
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影响因子：
5.8
作者：
Abriel, Hugues;Syam, Ninda;Rougier, Jean-Sebastien
通讯作者：
Rougier, Jean-Sebastien
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：
14.8
作者：
通讯作者：
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