TMC1 Forms the Pore of Mechanosensory Transduction Channels in Vertebrate Inner Ear Hair Cells.
TMC1 Forms the Pore of Mechanosensory Transduction Channels in Vertebrate Inner Ear Hair Cells.
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DOI：
10.1016/j.neuron.2018.07.033
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发表时间：
2018-08-22
期刊：
影响因子：
16.2
通讯作者：
Holt JR
中科院分区：
文献类型：
--
作者：
Pan B;Akyuz N;Liu XP;Asai Y;Nist-Lund C;Kurima K;Derfler BH;György B;Limapichat W;Walujkar S;Wimalasena LN;Sotomayor M;Corey DP;Holt JR
形成内耳毛细胞中机械感觉转导通道的渗透途径的蛋白质尚未被明确鉴定。遗传学、解剖学和生理学证据支持跨膜通道样蛋白（TMC）1在毛细胞感觉转导中的作用，但TMC蛋白的分子功能仍不清楚。在这里，我们提供的生化证据表明TMC 1组装为二聚体，沿着与结构和序列分析表明二聚体TMEM 16通道的相似性。为了鉴定TMC 1的孔区域，我们使用半胱氨酸诱变并在Tmc 1/2缺失小鼠的毛细胞中表达突变的TMC 1。半胱氨酸修饰试剂快速且不可逆地改变机械感觉转导的渗透性质。我们提出TMC 1在结构上类似于TMEM 16通道，并且包括十个跨膜结构域，其中四个结构域S4-S7排列在通道孔中。这些数据提供了令人信服的证据表明，TMC 1是听觉和前庭毛细胞中感觉转导通道的成孔成分。Pan等人使用生物化学、结构建模和毛细胞生理学来证明TMC 1残基排列在毛细胞感觉转导通道的孔中。
The proteins that form the permeation pathway of mechanosensory transduction channels in inner-ear hair cells have not been definitively identified. Genetic, anatomical, and physiological evidence support a role for transmembrane channel-like protein (TMC) 1 in hair cell sensory transduction, yet the molecular function of TMC proteins remains unclear. Here, we provide biochemical evidence suggesting TMC1 assembles as a dimer, along with structural and sequence analyses suggesting similarity to dimeric TMEM16 channels. To identify the pore region of TMC1, we used cysteine mutagenesis and expressed mutant TMC1 in hair cells of Tmc1/2-null mice. Cysteine-modification reagents rapidly and irreversibly altered permeation properties of mechanosensory transduction. We propose that TMC1 is structurally similar to TMEM16 channels and includes ten transmembrane domains with four domains, S4–S7, that line the channel pore. The data provide compelling evidence that TMC1 is a pore-forming component of sensory transduction channels in auditory and vestibular hair cells. Pan et al. used biochemistry, structural modeling, and hair-cell physiology to demonstrate that TMC1 residues line the pore of hair cell sensory transduction channels.
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影响因子：
14.9
作者：
Dobson L;Reményi I;Tusnády GE
通讯作者：
Tusnády GE
影响因子：
5.4
作者：
Hahn Y;Kim DS;Pastan IH;Lee B
通讯作者：
Lee B
影响因子：
3.4
作者：
Fettiplace R
通讯作者：
Fettiplace R
DOI：
10.1073/pnas.1606537113
发表时间：
2016-06-28
影响因子：
11.1
作者：
Guo, Yanmeng;Wang, Yuping;Wang, Zuoren
通讯作者：
Wang, Zuoren
影响因子：
3.6
作者：
Drenan, Ryan M.;Nashmi, Raad;Lester, Henry A.
通讯作者：
Lester, Henry A.