8z3f

Complex structure of CIB2 and TMC1 CR1

Structural highlights

8z3f is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.74Å
Ligands:	CA
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CIB2_MOUSE Calcium- and integrin-binding protein that plays a role in intracellular calcium homeostasis (PubMed:23023331, PubMed:28663585, PubMed:29084757, PubMed:29255404, PubMed:34089643). Acts as an auxiliary subunit of the sensory mechanoelectrical transduction (MET) channel in hair cells (PubMed:34089643). Essential for mechanoelectrical transduction (MET) currents in auditory hair cells and thereby required for hearing (PubMed:28663585, PubMed:29084757, PubMed:29255404). Regulates the function of hair cell mechanotransduction by controlling the distribution of transmembrane channel-like proteins TMC1 and TMC2, and by regulating the function of the MET channels in hair cells (PubMed:34089643). Required for the maintenance of auditory hair cell stereocilia bundle morphology and function and for hair-cell survival in the cochlea (PubMed:28663585, PubMed:29084757, PubMed:29255404). Critical for proper photoreceptor cell maintenance and function (PubMed:23023331). Plays a role in intracellular calcium homeostasis by decreasing ATP-induced calcium release (PubMed:23023331). Seems to be dispensable for vestibular functions (PubMed:29084757).^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

TMC1, a unique causative gene associated with deafness, exhibits variants with autosomal dominant and recessive inheritance patterns. TMC1 codes for the transmembrane channel-like protein 1 (TMC1), a key component of the mechano-electrical transduction (MET) machinery for hearing. However, the molecular mechanism of Ca(2+) regulation in MET remains unclear. Calcium and integrin-binding protein 2 (CIB2), another MET component associated with deafness, can bind with Ca(2+). Our study shows that TMC1-CIB2 complex undergoes a Ca(2+)-induced conformational change. We identified a vertebrate-specific binding site on TMC1 that interacts with apo CIB2, linked with hearing loss. Using an ex vivo mouse organotypic cochlea model, we demonstrated that disruption of the calcium-binding site of CIB2 perturbs the MET channel conductivity. After systematically analyzing the hearing loss variants, we observed dominant mutations of TMC1 cluster around the putative ion pore or at the binding interfaces with CIB2. These findings elucidate the molecular mechanisms underlying TMC1-linked hearing loss.

Mechano-electrical transduction components TMC1-CIB2 undergo a Ca(2+)-induced conformational change linked to hearing loss.,Wu S, Lin L, Hu Q, Yao X, Wang H, Liu S, Liu Q, Xi Y, Lin Y, Gong J, Hu R, Zhan W, Luo Y, He G, Liu Z, Xiong W, Wang Q, Xu Z, Bai F, Lu Q Dev Cell. 2025 Jan 24:S1534-5807(25)00004-8. doi: 10.1016/j.devcel.2025.01.004. PMID:39889697^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Riazuddin S, Belyantseva IA, Giese AP, Lee K, Indzhykulian AA, Nandamuri SP, Yousaf R, Sinha GP, Lee S, Terrell D, Hegde RS, Ali RA, Anwar S, Andrade-Elizondo PB, Sirmaci A, Parise LV, Basit S, Wali A, Ayub M, Ansar M, Ahmad W, Khan SN, Akram J, Tekin M, Riazuddin S, Cook T, Buschbeck EK, Frolenkov GI, Leal SM, Friedman TB, Ahmed ZM. Alterations of the CIB2 calcium syndrome type 1J and nonsyndromic deafness DFNB48. Nat Genet. 2012 Nov;44(11):1265-71. PMID:23023331 doi:10.1038/ng.2426
↑ Giese APJ, Tang YQ, Sinha GP, Bowl MR, Goldring AC, Parker A, Freeman MJ, Brown SDM, Riazuddin S, Fettiplace R, Schafer WR, Frolenkov GI, Ahmed ZM. CIB2 interacts with TMC1 and TMC2 and is essential for mechanotransduction in auditory hair cells. Nat Commun. 2017 Jun 29;8(1):43. PMID:28663585 doi:10.1038/s41467-017-00061-1
↑ Michel V, Booth KT, Patni P, Cortese M, Azaiez H, Bahloul A, Kahrizi K, Labbé M, Emptoz A, Lelli A, Dégardin J, Dupont T, Aghaie A, Oficjalska-Pham D, Picaud S, Najmabadi H, Smith RJ, Bowl MR, Brown SD, Avan P, Petit C, El-Amraoui A. CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival. EMBO Mol Med. 2017 Dec;9(12):1711-1731. PMID:29084757 doi:10.15252/emmm.201708087
↑ Wang Y, Li J, Yao X, Li W, Du H, Tang M, Xiong W, Chai R, Xu Z. Loss of CIB2 Causes Profound Hearing Loss and Abolishes Mechanoelectrical Transduction in Mice. Front Mol Neurosci. 2017 Dec 4;10:401. PMID:29255404 doi:10.3389/fnmol.2017.00401
↑ Liang X, Qiu X, Dionne G, Cunningham CL, Pucak ML, Peng G, Kim YH, Lauer A, Shapiro L, Muller U. CIB2 and CIB3 are auxiliary subunits of the mechanotransduction channel of hair cells. Neuron. 2021 Jul 7;109(13):2131-2149.e15. doi: 10.1016/j.neuron.2021.05.007. Epub, 2021 Jun 5. PMID:34089643 doi:https://dx.doi.org/10.1016/j.neuron.2021.05.007
↑ Wu S, Lin L, Hu Q, Yao X, Wang H, Liu S, Liu Q, Xi Y, Lin Y, Gong J, Hu R, Zhan W, Luo Y, He G, Liu Z, Xiong W, Wang Q, Xu Z, Bai F, Lu Q. Mechano-electrical transduction components TMC1-CIB2 undergo a Ca(2+)-induced conformational change linked to hearing loss. Dev Cell. 2025 Jan 24:S1534-5807(25)00004-8. PMID:39889697 doi:10.1016/j.devcel.2025.01.004

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Riazuddin S, Belyantseva IA, Giese AP, Lee K, Indzhykulian AA, Nandamuri SP, Yousaf R, Sinha GP, Lee S, Terrell D, Hegde RS, Ali RA, Anwar S, Andrade-Elizondo PB, Sirmaci A, Parise LV, Basit S, Wali A, Ayub M, Ansar M, Ahmad W, Khan SN, Akram J, Tekin M, Riazuddin S, Cook T, Buschbeck EK, Frolenkov GI, Leal SM, Friedman TB, Ahmed ZM. Alterations of the CIB2 calcium syndrome type 1J and nonsyndromic deafness DFNB48. Nat Genet. 2012 Nov;44(11):1265-71. PMID:23023331 doi:10.1038/ng.2426

[2] Giese APJ, Tang YQ, Sinha GP, Bowl MR, Goldring AC, Parker A, Freeman MJ, Brown SDM, Riazuddin S, Fettiplace R, Schafer WR, Frolenkov GI, Ahmed ZM. CIB2 interacts with TMC1 and TMC2 and is essential for mechanotransduction in auditory hair cells. Nat Commun. 2017 Jun 29;8(1):43. PMID:28663585 doi:10.1038/s41467-017-00061-1

[3] Michel V, Booth KT, Patni P, Cortese M, Azaiez H, Bahloul A, Kahrizi K, Labbé M, Emptoz A, Lelli A, Dégardin J, Dupont T, Aghaie A, Oficjalska-Pham D, Picaud S, Najmabadi H, Smith RJ, Bowl MR, Brown SD, Avan P, Petit C, El-Amraoui A. CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival. EMBO Mol Med. 2017 Dec;9(12):1711-1731. PMID:29084757 doi:10.15252/emmm.201708087

[4] Wang Y, Li J, Yao X, Li W, Du H, Tang M, Xiong W, Chai R, Xu Z. Loss of CIB2 Causes Profound Hearing Loss and Abolishes Mechanoelectrical Transduction in Mice. Front Mol Neurosci. 2017 Dec 4;10:401. PMID:29255404 doi:10.3389/fnmol.2017.00401

[5] Liang X, Qiu X, Dionne G, Cunningham CL, Pucak ML, Peng G, Kim YH, Lauer A, Shapiro L, Muller U. CIB2 and CIB3 are auxiliary subunits of the mechanotransduction channel of hair cells. Neuron. 2021 Jul 7;109(13):2131-2149.e15. doi: 10.1016/j.neuron.2021.05.007. Epub, 2021 Jun 5. PMID:34089643 doi:https://dx.doi.org/10.1016/j.neuron.2021.05.007

[6] Wu S, Lin L, Hu Q, Yao X, Wang H, Liu S, Liu Q, Xi Y, Lin Y, Gong J, Hu R, Zhan W, Luo Y, He G, Liu Z, Xiong W, Wang Q, Xu Z, Bai F, Lu Q. Mechano-electrical transduction components TMC1-CIB2 undergo a Ca(2+)-induced conformational change linked to hearing loss. Dev Cell. 2025 Jan 24:S1534-5807(25)00004-8. PMID:39889697 doi:10.1016/j.devcel.2025.01.004

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8z3f

Complex structure of CIB2 and TMC1 CR1

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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