CIB2 和 CIB3 是毛细胞机械转导通道的辅助亚基。
CIB2 and CIB3 are auxiliary subunits of the mechanotransduction channel of hair cells.
机构信息
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Biochemistry and Molecular Biophysics, Zuckerman Mind Brain, Department of Systems Biology, Columbia University, New York, NY 10032, USA.
出版信息
Neuron. 2021 Jul 7;109(13):2131-2149.e15. doi: 10.1016/j.neuron.2021.05.007. Epub 2021 Jun 5.
CIB2 is a Ca- and Mg-binding protein essential for mechanoelectrical transduction (MET) by cochlear hair cells, but not by vestibular hair cells that co-express CIB2 and CIB3. Here, we show that in cochlear hair cells, CIB3 can functionally substitute for CIB2. Using X-ray crystallography, we demonstrate that CIB2 and CIB3 are structurally similar to KChIP proteins, auxiliary subunits of voltage-gated K4 channels. CIB2 and CIB3 bind to TMC1/2 through a domain in TMC1/2 flanked by transmembrane domains 2 and 3. The co-crystal structure of the CIB-binding domain in TMC1 with CIB3 reveals that interactions are mediated through a conserved CIB hydrophobic groove, similar to KChIP1 binding of K4. Functional studies in mice show that CIB2 regulates TMC1/2 localization and function in hair cells, processes that are affected by deafness-causing CIB2 mutations. We conclude that CIB2 and CIB3 are MET channel auxiliary subunits with striking similarity to K4 channel auxiliary subunits.
CIB2 是一种钙和镁结合蛋白，对于耳蜗毛细胞的机电转导（MET）至关重要，但对于共同表达 CIB2 和 CIB3 的前庭毛细胞则不重要。在这里，我们表明 CIB3 可以在耳蜗毛细胞中替代 CIB2 发挥功能。通过 X 射线晶体学，我们证明 CIB2 和 CIB3 在结构上与 KChIP 蛋白相似，是电压门控 K4 通道的辅助亚基。CIB2 和 CIB3 通过 TMC1/2 中跨膜域 2 和 3 之间的一个结构域与 TMC1/2 结合。与 CIB3 的 TMC1 的 CIB 结合域的共晶结构表明，相互作用是通过保守的 CIB 疏水性凹槽介导的，类似于 KChIP1 与 K4 的结合。在小鼠中的功能研究表明，CIB2 调节毛细胞中 TMC1/2 的定位和功能，这些过程受致聋 CIB2 突变的影响。我们得出的结论是，CIB2 和 CIB3 是 MET 通道辅助亚基，与 K4 通道辅助亚基具有惊人的相似性。
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