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

被引：2

作者：

Giese, Arnaud P. J. ^{[1
]}

Weng, Wei-Hsiang ^{[2
,3
]}

Kindt, Katie S. ^{[4
]}

Chang, Hui Ho Vanessa ^{[5
]}

Montgomery, Jonathan S. ^{[2
,6
]}

Ratzan, Evan M. ^{[7
,8
]}

Beirl, Alisha J. ^{[4
]}

Aponte Rivera, Roberto ^{[4
]}

Lotthammer, Jeffrey M. ^{[2
]}

Walujkar, Sanket ^{[2
]}

Foster, Mark P. ^{[2
,3
,6
]}

Zobeiri, Omid A. ^{[9
]}

Holt, Jeffrey R. ^{[7
,8
]}

Riazuddin, Saima ^{[1
]}

Cullen, Kathleen E. ^{[10
,11
,12
]}

Sotomayor, Marcos ^{[2
,3
,6
,15
]}

Ahmed, Zubair M. ^{[1
,13
,14
]}

机构：

[1] Univ Maryland, Sch Med, Dept Otorhinolaryngol Head & Neck Surg, Baltimore, MD 21201 USA

[2] Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA

[3] Ohio State Univ, Biophys Grad Program, Columbus, OH 43210 USA

[4] Natl Inst Deafness & Other Commun Disorders, Sect Sensory Cell Dev & Funct, NIH, Bethesda, MD USA

[5] McGill Univ, Dept Physiol, Montreal, PQ, Canada

[6] Ohio State Univ, Ohio State Biochem Program, Columbus, OH 43220 USA

[7] Harvard Med Sch, Boston Childrens Hosp, FM Kirby Neurobiol Ctr, Dept Otolaryngol, Boston, MA USA

[8] Harvard Med Sch, Boston Childrens Hosp, FM Kirby Neurobiol Ctr, Dept Neurol, Boston, MA USA

[9] McGill Univ, Dept Biomed Engn, Montreal, PQ, Canada

[10] Johns Hopkins Univ Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD USA

[11] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD USA

[12] Johns Hopkins Univ, Sch Med, Dept Otolaryngol & Head & Neck Surg, Baltimore, MD USA

[13] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA

[14] Univ Maryland, Sch Med, Dept Ophthalmol & Visual Sci, Baltimore, MD 21201 USA

[15] Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA

来源：

ELIFE | 2025年 / 12卷

关键词：

zebrafish; CIB2; CIB3; mechanotransduction; TMC1; TMC2; TIP-LINK; MOLECULAR-DYNAMICS; TRANSMEMBRANE; CALCIUM; TRANSDUCTION; CADHERIN-23; PORE; TMIE; SIMULATIONS; EXPRESSION;

D O I：

10.7554/eLife.89719

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：35

共 8 条

[1] CIB2 interacts with TMC1 and TMC2 and is essential for mechanotransduction in auditory hair cells
Giese, Arnaud P. J.
Tang, Yi-Quan
Sinha, Ghanshyam P.
Bowl, Michael R.
Goldring, Adam C.
Parker, Andrew
Freeman, Mary J.
Brown, Steve D. M.
Riazuddin, Saima
Fettiplace, Robert
Schafer, William R.
Frolenkov, Gregory I.
Ahmed, Zubair M.
NATURE COMMUNICATIONS, 2017, 8
[2] CIB2 and CIB3 are auxiliary subunits of the mechanotransduction channel of hair cells
Liang, Xiaoping
Qiu, Xufeng
Dionne, Gilman
Cunningham, Christopher L.
Pucak, Michele L.
Peng, Guihong
Kim, Ye-Hyun
Lauer, Amanda
Shapiro, Lawrence
Mueller, Ulrich
NEURON, 2021, 109 (13) : 2131 - +
[3] Ectopic mouse TMC1 and TMC2 alone form mechanosensitive channels that are potently modulated by TMIE
Chen, Yixuan
Li, Yulin
Liu, Yonghong
Sun, Jiawen
Feng, Wanying
Chen, Yanfei
Tian, Ye
Lei, Tianlun
Huang, Pingbo
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2025, 122 (09)
[4] TMC1 and TMC2 Localize at the Site of Mechanotransduction in Mammalian Inner Ear Hair Cell Stereocilia
Kurima, Kiyoto
Ebrahim, Seham
Pan, Bifeng
Sedlacek, Miloslav
Sengupta, Prabuddha
Millis, Bryan A.
Cui, Runjia
Nakanishi, Hiroshi
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Griffith, Andrew J.
Kachar, Bechara
CELL REPORTS, 2015, 12 (10): : 1606 - 1617
[5] TMC1 and TMC2 Are Components of the Mechanotransduction Channel in Hair Cells of the Mammalian Inner Ear
Pan, Bifeng
Geleoc, Gwenaelle S.
Asai, Yukako
Horwitz, Geoffrey C.
Kurima, Kiyoto
Ishikawa, Kotaro
Kawashima, Yoshiyuki
Griffith, Andrew J.
Holt, Jeffrey R.
NEURON, 2013, 79 (03) : 504 - 515
[6] Structural relationship between the putative hair cell mechanotransduction channel TMC1 and TMEM16 proteins
Ballesteros, Angela
Fenollar-Ferrer, Cristina
Swartz, Kenton Jon
ELIFE, 2018, 7
[7] TMC1 and TMC2 Proteins Are Pore-Forming Subunits of Mechanosensitive Ion Channels
Jia, Yanyan
Zhao, Yimeng
Kusakizako, Tsukasa
Wang, Yao
Pan, Chengfang
Zhang, Yuwei
Nureki, Osamu
Hattori, Motoyuki
Yan, Zhiqiang
NEURON, 2020, 105 (02) : 310 - +
[8] Pdx-1 Activates Islet α- and β-Cell Proliferation via a Mechanism Regulated by Transient Receptor Potential Cation Channels 3 and 6 and Extracellular Signal-Regulated Kinases 1 and 2
Hayes, Heather L.
Moss, Larry G.
Schisler, Jonathan C.
Haldeman, Jonathan M.
Zhang, Zhushan
Rosenberg, Paul B.
Newgard, Christopher B.
Hohmeier, Hans E.
MOLECULAR AND CELLULAR BIOLOGY, 2013, 33 (20) : 4017 - 4029

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