Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA.
Nat Struct Mol Biol. 2010 Mar;17(3):339-47. doi: 10.1038/nsmb.1781. Epub 2010 Feb 28.
Vertebrate genomes encode 19 classical cadherins and about 100 nonclassical cadherins. Adhesion by classical cadherins depends on binding interactions in their N-terminal EC1 domains, which swap N-terminal beta-strands between partner molecules from apposing cells. However, strand-swapping sequence signatures are absent from nonclassical cadherins, raising the question of how these proteins function in adhesion. Here, we show that T-cadherin, a glycosylphosphatidylinositol (GPI)-anchored cadherin, forms dimers through an alternative nonswapped interface near the EC1-EC2 calcium-binding sites. Mutations within this interface ablate the adhesive capacity of T-cadherin. These nonadhesive T-cadherin mutants also lose the ability to regulate neurite outgrowth from T-cadherin-expressing neurons. Our findings reveal the likely molecular architecture of the T-cadherin homophilic interface and its requirement for axon outgrowth regulation. The adhesive binding mode used by T-cadherin may also be used by other nonclassical cadherins.
脊椎动物基因组编码 19 种经典钙黏蛋白和约 100 种非经典钙黏蛋白。经典钙黏蛋白的黏附依赖于其 N 端 EC1 结构域中的结合相互作用，该结构域在相邻细胞的伴侣分子之间交换 N 端β-链。然而，非经典钙黏蛋白中不存在链交换序列特征，这就提出了这些蛋白如何在黏附中发挥作用的问题。在这里，我们表明 T-钙黏蛋白，一种糖基磷脂酰肌醇 (GPI) 锚定钙黏蛋白，通过 EC1-EC2 钙结合位点附近的替代非交换界面形成二聚体。该界面内的突变会消除 T-钙黏蛋白的黏附能力。这些不具有黏附能力的 T-钙黏蛋白突变体也丧失了调节 T-钙黏蛋白表达神经元的神经突生长的能力。我们的发现揭示了 T-钙黏蛋白同源界面的可能分子结构及其对轴突生长调节的要求。T-钙黏蛋白使用的黏附结合模式也可能被其他非经典钙黏蛋白使用。
