Cryo-EM structures and functional properties of CALHM channels of the human placenta
Cryo-EM structures and functional properties of CALHM channels of the human placenta
复制标题
人胎盘CALHM通道的低温电镜结构和功能特性
DOI：
10.7554/elife.55853
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发表时间：
2020-05-06
期刊：
影响因子：
7.7
通讯作者：
Dutzler, Raimund
中科院分区：
文献类型：
--
作者：
Drozdzyk, Katarzyna;Sawicka, Marta;Dutzler, Raimund
物质通过胎盘的运输对胎儿的发育是必不可少的。在这里，我们感兴趣的钙稳态调节剂（CALHM）家族的通道在人类胎盘中的作用。通过转录分析，我们发现旁系同源物CALHM 2、4和6在该器官中高度表达，并且在滋养层分化过程中上调。基于电生理学，我们观察到这些旁系同源物的激活不同于电压门控和钙门控通道CALHM 1。CALHM 4的冷冻-EM结构显示具有大圆柱形孔的十聚体和十一聚体组件，而在CALHM 6中，构象变化已将孔形状转换成在细胞内侧变窄的圆锥，从而描述通道的不同功能状态。孔的几何形状改变了分布的脂质，占据圆柱形孔的CALHM 4在一个双层样的安排，而他们重新分布在圆锥形孔的CALHM 6与潜在的功能后果。
The transport of substances across the placenta is essential for the development of the fetus. Here, we were interested in the role of channels of the calcium homeostasis modulator (CALHM) family in the human placenta. By transcript analysis, we found the paralogs CALHM2, 4, and 6 to be highly expressed in this organ and upregulated during trophoblast differentiation. Based on electrophysiology, we observed that activation of these paralogs differs from the voltage- and calcium-gated channel CALHM1. Cryo-EM structures of CALHM4 display decameric and undecameric assemblies with large cylindrical pore, while in CALHM6 a conformational change has converted the pore shape into a conus that narrows at the intracellular side, thus describing distinct functional states of the channel. The pore geometry alters the distribution of lipids, which occupy the cylindrical pore of CALHM4 in a bilayer-like arrangement whereas they have redistributed in the conical pore of CALHM6 with potential functional consequences.