Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210.
Cold Spring Harb Perspect Biol. 2018 Sep 4;10(9):a029280. doi: 10.1101/cshperspect.a029280.
Cadherins form a large family of proteins often involved in calcium-dependent cellular adhesion. Although classical members of the family can provide a physical bond between cells, a subset of special cadherins use their extracellular domains to interlink apical specializations of single epithelial sensory cells. Two of these cadherins, cadherin-23 (CDH23) and protocadherin-15 (PCDH15), form extracellular "tip link" filaments that connect apical bundles of stereocilia on hair cells essential for inner-ear mechanotransduction. As these bundles deflect in response to mechanical stimuli from sound or head movements, tip links gate hair-cell mechanosensitive channels to initiate sensory perception. Here, we review the unusual and diverse structural properties of these tip-link cadherins and the functional significance of their deafness-related missense mutations. Based on the structural features of CDH23 and PCDH15, we discuss the elasticity of tip links and models that bridge the gap between the nanomechanics of cadherins and the micromechanics of hair-cell bundles during inner-ear mechanotransduction.
钙黏蛋白构成了一个庞大的蛋白质家族，通常参与钙依赖性细胞黏附。尽管该家族的经典成员可以为细胞之间提供物理连接，但一组特殊的钙黏蛋白利用其细胞外结构域将单个上皮感觉细胞的顶端特化结构连接起来。这些钙黏蛋白中的两种，钙黏蛋白-23（CDH23）和原钙黏蛋白-15（PCDH15），形成了细胞外的“尖端连接”丝，连接着毛细胞中对内耳机械转导至关重要的静纤毛顶端束。当这些束因声音或头部运动产生的机械刺激而偏转时，尖端连接使毛细胞机械敏感通道门控，从而引发感觉感知。在这里，我们回顾了这些尖端连接钙黏蛋白的不寻常和多样化的结构特性，以及它们与耳聋相关的错义突变的功能意义。基于 CDH23 和 PCDH15 的结构特征，我们讨论了尖端连接的弹性以及在内耳机械转导过程中，连接钙黏蛋白的纳米力学和毛细胞束的微力学之间的模型。
