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脊椎动物的TMC1/2和CIB2/3蛋白复合物形成毛细胞机械转导阳离子通道。

Complexes of vertebrate TMC1/2 and CIB2/3 proteins form hair-cell mechanotransduction cation channels.

作者信息

Giese Arnaud P J, Weng Wei-Hsiang, Kindt Katie S, Chang Hui Ho Vanessa, Montgomery Jonathan S, Ratzan Evan M, Beirl Alisha J, Aponte Rivera Roberto, Lotthammer Jeffrey M, Walujkar Sanket, Foster Mark P, Zobeiri Omid A, Holt Jeffrey R, Riazuddin Saima, Cullen Kathleen E, Sotomayor Marcos, Ahmed Zubair M

机构信息

Department of Otorhinolaryngology - Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, United States.

Department of Chemistry and Biochemistry, The Ohio State University, Columbus, United States.

出版信息

Elife. 2025 Jan 8;12:RP89719. doi: 10.7554/eLife.89719.

DOI:10.7554/eLife.89719
PMID:39773557
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11709434/
Abstract

Calcium and integrin-binding protein 2 (CIB2) and CIB3 bind to transmembrane channel-like 1 (TMC1) and TMC2, the pore-forming subunits of the inner-ear mechano-electrical transduction (MET) apparatus. These interactions have been proposed to be functionally relevant across mechanosensory organs and vertebrate species. Here, we show that both CIB2 and CIB3 can form heteromeric complexes with TMC1 and TMC2 and are integral for MET function in mouse cochlea and vestibular end organs as well as in zebrafish inner ear and lateral line. Our AlphaFold 2 models suggest that vertebrate CIB proteins can simultaneously interact with at least two cytoplasmic domains of TMC1 and TMC2 as validated using nuclear magnetic resonance spectroscopy of TMC1 fragments interacting with CIB2 and CIB3. Molecular dynamics simulations of TMC1/2 complexes with CIB2/3 predict that TMCs are structurally stabilized by CIB proteins to form cation channels. Overall, our work demonstrates that intact CIB2/3 and TMC1/2 complexes are integral to hair-cell MET function in vertebrate mechanosensory epithelia.

摘要

钙整合素结合蛋白2（CIB2）和CIB3与跨膜通道样蛋白1（TMC1）和TMC2结合，TMC1和TMC2是内耳机械电转导（MET）装置的成孔亚基。这些相互作用被认为在跨机械感觉器官和脊椎动物物种中具有功能相关性。在这里，我们表明CIB2和CIB3都可以与TMC1和TMC2形成异源复合物，并且对于小鼠耳蜗和前庭终器以及斑马鱼内耳和侧线中的MET功能是不可或缺的。我们的AlphaFold 2模型表明，脊椎动物的CIB蛋白可以同时与TMC1和TMC2的至少两个胞质结构域相互作用，这一点通过与CIB2和CIB3相互作用的TMC1片段的核磁共振光谱得到了验证。TMC1/2与CIB2/3复合物的分子动力学模拟预测，TMCs通过CIB蛋白在结构上稳定以形成阳离子通道。总体而言，我们的工作表明完整的CIB2/3和TMC1/2复合物对于脊椎动物机械感觉上皮细胞中的毛细胞MET功能是不可或缺的。

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Front Mol Neurosci. 2023 Nov 14;16:1274822. doi: 10.3389/fnmol.2023.1274822. eCollection 2023.
2
CIB2 and CIB3 Regulate Stereocilia Maintenance and Mechanoelectrical Transduction in Mouse Vestibular Hair Cells.CIB2 和 CIB3 调节小鼠前庭毛细胞的静纤毛维持和机械电转导。
J Neurosci. 2023 May 3;43(18):3219-3231. doi: 10.1523/JNEUROSCI.1807-22.2023. Epub 2023 Mar 31.
3
The tetraspan LHFPL5 is critical to establish maximal force sensitivity of the mechanotransduction channel of cochlear hair cells.
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Commun Biol. 2025 May 13;8(1):742. doi: 10.1038/s42003-025-07943-x.
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