CIB2 as a Ca2+ Sensor for Auditory Mechano-Electrical Transduction and Linked to Genetic-Heterogeneity of TMC1 in Hearing Loss

Wu, S.; Lin, L.; Hu, Q.; Yao, X.; Wang, H.; Liu, S.; Liu, Q.; Lu, L.; 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.

doi:10.1101/2024.07.24.604958

bioRxiv · 10.1101/2024.07.24.604958

CIB2 as a Ca2+ Sensor for Auditory Mechano-Electrical Transduction and Linked to Genetic-Heterogeneity of TMC1 in Hearing Loss

Wu, S.·Lin, L.·Hu, Q.·Yao, X.·Wang, H.·Liu, S.·Liu, Q.·Lu, L.·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.

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Abstract

Non-syndromic sensorineural hearing loss is characterized by genetic heterogeneity, leading to potential clinical misdiagnosis. TMC1, a unique causative gene associated with deafness, exhibits variants with autosomal dominant and recessive inheritance patterns. TMC1 codes for the transmembrane channel-like 1 (TMC1), a key component of the mechano-electrical transduction (MET) machinery for hearing. However, the molecular mechanism of Ca2+ regulation in MET, which is essential for sound perception, remains unclear. CIB2, another MET component associated with deafness, can bind with calcium and may play a role in MET gating. Our study reveals that the TMC1-CIB2 complex undergoes a Ca2+-induced conformational change, highlighting the crucial role of Ca2+ in MET. We identified a vertebrate-specific binding site on TMC1, named CR3, that interacts with apo CIB2, with the binding interface linked to hearing loss. Using an in-vivo animal model, we demonstrated that disruption of the calcium-sensing site of CIB2 perturbs the MET channel conductivity, confirming its role as a Ca2+ sensor for MET. Additionally, after systematically analyzing the hearing-loss variants, we observed that dominant mutations of TMC1 are often located near the ion pore or at the binding interfaces with the Ca2+ sensor CIB2. This provides a detailed mechanism of the genetic heterogeneity of TMC1 in hearing loss at an atomic level.

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Wu, S., Lin, L., Hu, Q., Yao, X., Wang, H., Liu, S., Liu, Q., Lu, L., 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.. 2024-07-24. CIB2 as a Ca2+ Sensor for Auditory Mechano-Electrical Transduction and Linked to Genetic-Heterogeneity of TMC1 in Hearing Loss. https://doi.org/10.1101/2024.07.24.604958

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