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核心技术专利：CN118964589B侵权必究
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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, Rivera Roberto Aponte, 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, MD, USA.

Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA.

出版信息

bioRxiv. 2024 Jul 5:2023.05.26.542533. doi: 10.1101/2023.05.26.542533.

DOI:10.1101/2023.05.26.542533
PMID:37398045
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10312449/
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整个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，这通过使用与CIB2和CIB3相互作用的TMC1片段的核磁共振光谱得到验证。TMC1/2与CIB2/3复合物的分子动力学模拟预测，TMC通过CIB蛋白在结构上得到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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d989/11229166/4436b15f79d0/nihpp-2023.05.26.542533v2-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d989/11229166/e5982f01fab2/nihpp-2023.05.26.542533v2-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d989/11229166/32559182c0b2/nihpp-2023.05.26.542533v2-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d989/11229166/0e53b942bc82/nihpp-2023.05.26.542533v2-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d989/11229166/09de172bcad6/nihpp-2023.05.26.542533v2-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d989/11229166/2a8723d18fb6/nihpp-2023.05.26.542533v2-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d989/11229166/3f6a5c9e974e/nihpp-2023.05.26.542533v2-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d989/11229166/cb5abefa70e2/nihpp-2023.05.26.542533v2-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d989/11229166/4436b15f79d0/nihpp-2023.05.26.542533v2-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d989/11229166/e5982f01fab2/nihpp-2023.05.26.542533v2-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d989/11229166/32559182c0b2/nihpp-2023.05.26.542533v2-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d989/11229166/0e53b942bc82/nihpp-2023.05.26.542533v2-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d989/11229166/09de172bcad6/nihpp-2023.05.26.542533v2-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d989/11229166/2a8723d18fb6/nihpp-2023.05.26.542533v2-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d989/11229166/3f6a5c9e974e/nihpp-2023.05.26.542533v2-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d989/11229166/cb5abefa70e2/nihpp-2023.05.26.542533v2-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d989/11229166/4436b15f79d0/nihpp-2023.05.26.542533v2-f0008.jpg

相似文献

[1]
Complexes of vertebrate TMC1/2 and CIB2/3 proteins form hair-cell mechanotransduction cation channels.

bioRxiv. 2024-7-5

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

Elife. 2025-1-8

[3]
CIB2 and CIB3 are auxiliary subunits of the mechanotransduction channel of hair cells.

Neuron. 2021-7-7

[4]
Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes.

J Clin Invest. 2011-11-21

[5]
Structural insights into calcium-dependent CIB2-TMC1 interaction in hair cell mechanotransduction.

Commun Biol. 2025-2-25

[6]
TMC1 Forms the Pore of Mechanosensory Transduction Channels in Vertebrate Inner Ear Hair Cells.

Neuron. 2018-8-22

[7]
Mechano-electrical transduction components TMC1-CIB2 undergo a Ca-induced conformational change linked to hearing loss.

Dev Cell. 2025-6-9

[8]
Disruption of Genes in Zebrafish Reveals Subunit Requirements in Subtypes of Inner Ear Hair Cells.

J Neurosci. 2020-5-5

[9]
CIB2 and CIB3 Regulate Stereocilia Maintenance and Mechanoelectrical Transduction in Mouse Vestibular Hair Cells.

J Neurosci. 2023-5-3

[10]
TMC1 and TMC2 are components of the mechanotransduction channel in hair cells of the mammalian inner ear.

Neuron. 2013-7-18

引用本文的文献

[1]
Differential expression of mechanotransduction complex genes in auditory/vestibular hair cells in zebrafish.

Front Mol Neurosci. 2023-11-14

本文引用的文献

[1]
Differential expression of mechanotransduction complex genes in auditory/vestibular hair cells in zebrafish.

Front Mol Neurosci. 2023-11-14

[2]
CIB2 and CIB3 Regulate Stereocilia Maintenance and Mechanoelectrical Transduction in Mouse Vestibular Hair Cells.

J Neurosci. 2023-5-3

[3]
The tetraspan LHFPL5 is critical to establish maximal force sensitivity of the mechanotransduction channel of cochlear hair cells.

Cell Rep. 2023-3-28

[4]
Asymmetric mechanotransduction by hair cells of the zebrafish lateral line.

Curr Biol. 2023-4-10

[5]
Single-cell transcriptomic profiling of the zebrafish inner ear reveals molecularly distinct hair cell and supporting cell subtypes.

Elife. 2023-1-4

[6]
Structures of the TMC-1 complex illuminate mechanosensory transduction.

Nature. 2022-10

[7]
The conductance and organization of the TMC1-containing mechanotransducer channel complex in auditory hair cells.

Proc Natl Acad Sci U S A. 2022-10-11

[8]
Mechanical gating of the auditory transduction channel TMC1 involves the fourth and sixth transmembrane helices.

Sci Adv. 2022-7-15

[9]
Single-cell transcriptome analysis reveals three sequential phases of gene expression during zebrafish sensory hair cell regeneration.

Dev Cell. 2022-3-28

[10]
The speed of the hair cell mechanotransducer channel revealed by fluctuation analysis.

J Gen Physiol. 2021-10-4

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