Cryo-EM structure of an open conformation of a gap junction hemichannel in lipid bilayer nanodiscs.
Cryo-EM structure of an open conformation of a gap junction hemichannel in lipid bilayer nanodiscs.
复制标题
DOI：
10.1016/j.str.2021.05.010
复制
发表时间：
2021-09-02
期刊：
影响因子：
5.7
通讯作者：
Yeager, Mark
中科院分区：
文献类型：
--
作者：
Khan, Ali K.;Jagielnicki, Maciej;Bennett, Brad C.;Purdy, Michael D.;Yeager, Mark
为了介导通过间隙连接通道（GJC）的细胞间通讯，连接蛋白（Cx）作为六聚体半通道运输至质膜，其在相邻细胞膜之间端对端对接，从而形成十二聚体细胞间管道。半通道还独立地起作用以介导内容物在细胞质和细胞外空间之间的通过。为了产生半通道，将突变N176 Y引入Cx 26的第二胞外环。在脂质双层纳米盘中的六聚体半通道的电子低温显微镜结构显示开孔和4-螺旋束跨膜设计，其与十二聚体GJC几乎相同。与跨膜α-螺旋的高分辨率相反，细胞外环的分辨率较低。细胞外环的构象灵活性可能是必不可少的，以促进监视在并列细胞中的半通道，以确定兼容的Cx亚型，使细胞间的对接。我们的研究结果也提供了以前的电生理和渗透研究的Cx半通道的结构基础。Khan等人报告了Cx 26间隙连接半通道的冷冻-EM结构，并揭示了与对接的GJC相比，每个亚基内的4-螺旋束和开孔结构的保守性。与GJC不同，细胞外环显示构象灵活性，这可能有助于监视和对接并置细胞中的相容半通道。
To mediate cell-to-cell communication via gap junction channels (GJCs), connexins (Cx) traffic as hexameric hemichannels to the plasma membrane, which dock end-to-end between adjacent cell membranes, thereby forming a dodecameric intercellular conduit. Hemichannels also function independently to mediate the passage of contents between the cytoplasm and extracellular space. To generate hemichannels, the mutation N176Y was introduced into the second extracellular loop of Cx26. The electron cryomicroscopy structure of the hexameric hemichannel in lipid bilayer nanodiscs displays an open pore and a 4-helix bundle transmembrane design that is nearly identical to dodecameric GJCs. In contrast to the high resolution of the transmembrane a-helices, the extracellular loops are less well resolved. The conformational flexibility of the extracellular loops may be essential to facilitate surveillance of hemichannels in apposed cells to identify compatible Cx isoforms that enable intercellular docking. Our results also provide a structural foundation for previous electrophysiologic and permeation studies of Cx hemichannels. Khan et al. report the cryo-EM structure of a Cx26 gap junction hemichannel and reveal conservation in the 4-helix bundle within each subunit and the open pore structure compared with the docked GJC. Unlike GJCs, the extracellular loops display conformational flexibility, which may facilitate surveillance and docking of compatible hemichannels in apposed cells.
登录
查看更多内容
影响因子：
48
作者：
Kucukelbir, Alp;Sigworth, Fred J.;Tagare, Hemant D.
通讯作者：
Tagare, Hemant D.
影响因子：
4
作者：
Bygrave, FL;Benedetti, A
通讯作者：
Benedetti, A
影响因子：
3
作者：
de la Rosa-Trevin, J. M.;Quintana, A.;Carazo, J. M.
通讯作者：
Carazo, J. M.
影响因子：
13.6
作者：
Lee, Hyuk-Joon;Jeong, Hyeongseop;Woo, Jae-Sung
通讯作者：
Woo, Jae-Sung
影响因子：
3.7
作者：
Ambrosi C;Walker AE;Depriest AD;Cone AC;Lu C;Badger J;Skerrett IM;Sosinsky GE
通讯作者：
Sosinsky GE