Structural relationship between the putative hair cell mechanotransduction channel TMC1 and TMEM16 proteins.
Structural relationship between the putative hair cell mechanotransduction channel TMC1 and TMEM16 proteins.
复制标题
假定的毛细胞机械转导通道 TMC1 和 TMEM16 蛋白之间的结构关系。
DOI：
10.7554/elife.38433
复制
发表时间：
2018-07-31
期刊：
影响因子：
7.7
通讯作者：
Swartz KJ
中科院分区：
文献类型：
--
作者：
Ballesteros A;Fenollar-Ferrer C;Swartz KJ
毛细胞机械转导（MET）通道复合物对听力至关重要，但其分子身份和结构尚不清楚。跨膜通道样1 （TMC1）蛋白定位于MET通道的位置，与负责机械门控的尖端链接相互作用，TMC1的遗传改变改变MET通道的特性并导致耳聋，支持TMC1形成MET通道的假设。我们基于TMEM16蛋白的x射线和低温电镜结构建立了一个TMC1模型，揭示了在蛋白-脂质界面附近存在一个大空腔，也包含了Beethoven突变，这表明它可能是一个渗透途径。我们还发现毛细胞对3kda葡聚糖具有渗透性，葡聚糖的渗透需要TMC1/2蛋白和功能性MET通道，这支持了大渗透途径的存在和TMC1是MET通道复合物的孔形成亚基的假设。
The hair cell mechanotransduction (MET) channel complex is essential for hearing, yet it’s molecular identity and structure remain elusive. The transmembrane channel–like 1 (TMC1) protein localizes to the site of the MET channel, interacts with the tip-link responsible for mechanical gating, and genetic alterations in TMC1 alter MET channel properties and cause deafness, supporting the hypothesis that TMC1 forms the MET channel. We generated a model of TMC1 based on X-ray and cryo-EM structures of TMEM16 proteins, revealing the presence of a large cavity near the protein-lipid interface that also harbors the Beethoven mutation, suggesting that it could function as a permeation pathway. We also find that hair cells are permeable to 3 kDa dextrans, and that dextran permeation requires TMC1/2 proteins and functional MET channels, supporting the presence of a large permeation pathway and the hypothesis that TMC1 is a pore forming subunit of the MET channel complex.