Molecular basis of sidekick-mediated cell-cell adhesion and specificity
Molecular basis of sidekick-mediated cell-cell adhesion and specificity
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DOI：
10.7554/elife.19058
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发表时间：
2016-09-19
期刊：
影响因子：
7.7
通讯作者：
Shapiro, Lawrence
中科院分区：
文献类型：
--
作者：
Goodman, Kerry M.;Yamagata, Masahito;Shapiro, Lawrence
Sidekick (Sdk) 1和2是相关的免疫球蛋白超家族细胞粘附蛋白，是视网膜神经元特定亚型之间适当突触连接所必需的。Sdks介导细胞与细胞间的粘附，具有特异性，这是其神经元靶向功能的基础。在这里，我们报道了Sdk1和Sdk2外结构域区域的晶体结构，揭示了由四个n端免疫球蛋白结构域（Ig1-4）介导的相似的同型二聚体，它们排列成马蹄形。这些Ig1-4马蹄铁通过Ig1:Ig2、Ig1:Ig1和Ig3:Ig4相互作用，在两种同型二聚体中以一种新的背对背方向相互作用。结构导向的突变结果表明，这种典型二聚体对于Sdk介导的细胞聚集（通过反式相互作用）和分离细胞中的Sdk聚集（通过顺式相互作用）都是必需的。Sdk1/Sdk2识别特异性通过Ig1-4编码，Ig1-2赋予大部分结合亲和力和差异特异性。我们认为顺式和反式相互作用之间的竞争提供了一种新的机制来提高细胞-细胞相互作用的特异性。
Sidekick (Sdk) 1 and 2 are related immunoglobulin superfamily cell adhesion proteins required for appropriate synaptic connections between specific subtypes of retinal neurons. Sdks mediate cell-cell adhesion with homophilic specificity that underlies their neuronal targeting function. Here we report crystal structures of Sdk1 and Sdk2 ectodomain regions, revealing similar homodimers mediated by the four N-terminal immunoglobulin domains (Ig1-4), arranged in a horseshoe conformation. These Ig1-4 horseshoes interact in a novel back-to-back orientation in both homodimers through Ig1:Ig2, Ig1:Ig1 and Ig3:Ig4 interactions. Structure-guided mutagenesis results show that this canonical dimer is required for both Sdk-mediated cell aggregation (via trans interactions) and Sdk clustering in isolated cells (via cis interactions). Sdk1/Sdk2 recognition specificity is encoded across Ig1-4, with Ig1-2 conferring the majority of binding affinity and differential specificity. We suggest that competition between cis and trans interactions provides a novel mechanism to sharpen the specificity of cell-cell interactions.