Li Yahong, Chen Jiasheng, Jiang Wenli, Ye Jin, Zhang Xuan, Wang Chao
Department of Neurology, the First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Ministry of Education Key Laboratory for Membrane-less Organelles and Cellular Dynamics, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, China.
Commun Biol. 2025 Feb 25;8(1):306. doi: 10.1038/s42003-025-07761-1.
Calcium- and integrin-binding protein 2 (CIB2) plays a crucial role in mechanoelectrical transduction (MET) in cochlear hair cells, particularly in modulating the function and localization of the core components of MET channels TMC1/2. CIB2, along with its homolog CIB3, interacts with TMC1/2 through two distinct sites. Here, our study unveils CIB2/3's role as a calcium sensor in its interaction with TMC1. Utilizing X-ray crystallography, we elucidate the high-resolution structure of the mammalian CIB2-TMC1 complex. Structural analyses reveal that cation-bound CIB2 forms a negatively charged surface that aligns with a positively charged surface on the TMC1 N-terminus. Moreover, our data suggest that Ca²⁺ modulates CIB2's interaction with both the N-terminal domain and the loop 1 region of TMC1, and that Ca²⁺-bound CIB2 is capable of simultaneously binding to both regions of TMC1. Critically, we examine pathogenic variants of CIB2 associated with hearing loss, discovering that these variants have differential impacts on CIB2's interactions with TMC1's dual binding sites, displaying diminished calcium-binding affinities for several of these CIB2 mutations. These findings provide a deeper understanding of the molecular mechanisms underlying CIB2 function and its implications in hearing loss, offering potential avenues for therapeutic interventions in deafness.
钙整合素结合蛋白2（CIB2）在耳蜗毛细胞的机械电转导（MET）中起关键作用，特别是在调节MET通道TMC1/2核心成分的功能和定位方面。CIB2与其同源物CIB3通过两个不同位点与TMC1/2相互作用。在此，我们的研究揭示了CIB2/3在与TMC1相互作用中作为钙传感器的作用。利用X射线晶体学，我们阐明了哺乳动物CIB2-TMC1复合物的高分辨率结构。结构分析表明，结合阳离子的CIB2形成一个带负电荷的表面，该表面与TMC1 N端的带正电荷表面对齐。此外，我们的数据表明Ca²⁺调节CIB2与TMC1 N端结构域和环1区域的相互作用，并且结合Ca²⁺的CIB2能够同时结合TMC1的这两个区域。至关重要的是，我们研究了与听力损失相关的CIB2致病变体，发现这些变体对CIB2与TMC1双重结合位点的相互作用有不同影响，其中一些CIB2突变显示出钙结合亲和力降低。这些发现为深入理解CIB2功能的分子机制及其在听力损失中的影响提供了依据，为耳聋的治疗干预提供了潜在途径。
