Cadherin-23,一种巨大的非典型钙粘蛋白,在上皮细胞的细胞-细胞连接处形成嗜性相互作用,并在神经上皮细胞的尖端与protocadherin-15形成嗜性相互作用。虽然异二聚体的分子结构得到解决,同型二聚体结构尚待解决。同二聚体在细胞-细胞粘附中起着至关重要的作用,因为在癌症中钙黏着蛋白-23的下调会使细胞间连接松动,从而导致癌细胞的更快迁移和患者生存率的显着下降。与典型的E-钙粘蛋白相比,体外研究已经测量了钙粘蛋白-23的更强的聚集倾向。这里,我们破译了钙粘蛋白-23在溶液中独特的反式-同二聚体结构,并表明它由两个基于静电的界面组成,扩展到两个终端域。接口是强大的,具有~8x10-4s-1的低解离率,支持其强聚集倾向。我们发现了点突变,E78K,破坏了这种绑定。有趣的是,据报道,皮肤癌发生了界面突变。总的来说,强钙黏着蛋白-23粘附的结构基础可能在机械生物学和癌症领域具有深远的应用。
Cadherin-23, a giant atypical cadherin, forms homophilic interactions at the cell-cell junction of epithelial cells and heterophilic interactions with protocadherin-15 at the tip-links of neuroepithelial cells. While the molecular structure of the heterodimer is solved, the homodimer structure is yet to be resolved. The homodimers play an essential role in cell-cell adhesion as the downregulation of cadherin-23 in cancers loosen the intercellular junction resulting in faster-migration of cancer cells and a significant drop in patient survival. In vitro studies have measured a stronger aggregation-propensity of cadherin-23 compared to typical E-cadherin. Here, we deciphered the unique trans-homodimer structure of cadherin-23 in solution, and show that it consists of two electrostatic-based interfaces extended up to two terminal domains. The interface is robust, with a low off-rate of ~8x10-4 s-1 that supports its strong aggregation-propensity. We identified a point-mutation, E78K, that disrupts this binding. Interestingly, a mutation at the interface was reported in skin cancer. Overall, the structural basis of the strong cadherin-23 adhesion may have far-reaching applications in the fields of mechanobiology and cancer.