TMC1 和 TMC2 蛋白是机械敏感离子通道的孔形成亚基。
TMC1 and TMC2 Proteins Are Pore-Forming Subunits of Mechanosensitive Ion Channels.
机构信息
State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Department of Neurosurgery at Huashan Hospital, Human Phenome Institute, Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, Institute of Brain Science, Department of Physiology and Biophysics, School of Life Sciences, Fudan University, 2005 Songhu Road, Yangpu District, Shanghai 200438, China.
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Multiscale Research Institute for Complex Systems, Department of Physiology and Biophysics, School of Life Sciences, Fudan University, Shanghai 200438, China.
出版信息
Neuron. 2020 Jan 22;105(2):310-321.e3. doi: 10.1016/j.neuron.2019.10.017. Epub 2019 Nov 21.
Transmembrane channel-like (TMC) 1 and 2 are required for the mechanotransduction of mouse inner ear hair cells and localize to the site of mechanotransduction in mouse hair cell stereocilia. However, it remains unclear whether TMC1 and TMC2 are indeed ion channels and whether they can sense mechanical force directly. Here we express TMC1 from the green sea turtle (CmTMC1) and TMC2 from the budgerigar (MuTMC2) in insect cells, purify and reconstitute the proteins, and show that liposome-reconstituted CmTMC1 and MuTMC2 proteins possess ion channel activity. Furthermore, by applying pressure to proteoliposomes, we demonstrate that both CmTMC1 and MuTMC2 proteins can indeed respond to mechanical stimuli. In addition, CmTMC1 mutants corresponding to human hearing loss mutants exhibit reduced or no ion channel activity. Taken together, our results show that the CmTMC1 and MuTMC2 proteins are pore-forming subunits of mechanosensitive ion channels, supporting TMC1 and TMC2 as hair cell transduction channels.
跨膜通道样蛋白 1 和 2（TMC1 和 TMC2）对于小鼠内耳毛细胞的力感受是必需的，并且定位于毛细胞静纤毛的力感受部位。然而，TMC1 和 TMC2 是否确实是离子通道，以及它们是否可以直接感受机械力，目前仍不清楚。在这里，我们在昆虫细胞中表达了绿海龟的 TMC1（CmTMC1）和虎皮鹦鹉的 TMC2（MuTMC2），并对这些蛋白进行了纯化和重构，结果表明脂质体重构的 CmTMC1 和 MuTMC2 蛋白具有离子通道活性。此外，通过对蛋白脂质体施加压力，我们证明了 CmTMC1 和 MuTMC2 蛋白确实可以对机械刺激做出反应。此外，与人的听力损失突变体相对应的 CmTMC1 突变体表现出降低或没有离子通道活性。总之，我们的结果表明 CmTMC1 和 MuTMC2 蛋白是机械敏感离子通道的孔形成亚基，支持 TMC1 和 TMC2 作为毛细胞转导通道。
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