Wu Shaoxuan, Lin Lin, Hu Qiaoyu, Yao Xuebo, Wang Hongyang, Liu Shuang, Liu Qingling, Xi Yuehui, Lin Yuzhe, Gong Jianqiao, Hu Ruixing, Zhan Wei, Luo Yi, He Guang, Liu Zhijun, Xiong Wei, Wang Qiuju, Xu Zhigang, Bai Fang, Lu Qing
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, China.
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China; Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai 200062, China.
Dev Cell. 2025 Jun 9;60(11):1586-1600.e4. doi: 10.1016/j.devcel.2025.01.004. Epub 2025 Jan 30.
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 regulation in MET remains unclear. Calcium and integrin-binding protein 2 (CIB2), another MET component associated with deafness, can bind with Ca. Our study shows that TMC1-CIB2 complex undergoes a Ca-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.
TMC1是一种与耳聋相关的独特致病基因，表现出常染色体显性和隐性遗传模式的变异。TMC1编码跨膜通道样蛋白1（TMC1），它是听觉机械电转导（MET）机制的关键组成部分。然而，MET中钙调节的分子机制仍不清楚。钙和整合素结合蛋白2（CIB2）是另一种与耳聋相关的MET成分，它能与钙结合。我们的研究表明，TMC1-CIB2复合物会发生钙诱导的构象变化。我们在TMC1上鉴定出一个与脱辅基CIB2相互作用的脊椎动物特异性结合位点，这与听力损失有关。利用离体小鼠耳蜗器官型模型，我们证明破坏CIB2的钙结合位点会扰乱MET通道的传导性。在系统分析听力损失变异后，我们观察到TMC1的显性突变聚集在假定的离子孔周围或与CIB2的结合界面处。这些发现阐明了TMC1相关听力损失的分子机制。
