Structural Basis of Diverse Homophilic Recognition by Clustered α- and β-Protocadherins.
Structural Basis of Diverse Homophilic Recognition by Clustered α- and β-Protocadherins.
复制标题
DOI：
10.1016/j.neuron.2016.04.004
复制
发表时间：
2016-05-18
期刊：
影响因子：
16.2
通讯作者：
Shapiro L
中科院分区：
文献类型：
--
作者：
Goodman KM;Rubinstein R;Thu CA;Bahna F;Mannepalli S;Ahlsén G;Rittenhouse C;Maniatis T;Honig B;Shapiro L
突变的原钙粘蛋白（α-、β-和γ-Pcdhs）为个体脊椎动物神经元提供高水平的细胞表面多样性，参与高度特异性的嗜同性相互作用以介导哺乳动物神经回路发育中的重要作用。Pcdhs如何通过它们的细胞外钙粘蛋白（EC）结构域在几十种高度相似的亚型中进行同源结合尚未确定。在这里，我们报告了四种小鼠Pcdh亚型（α4，α7，β6和β8）的胞外区的晶体结构，揭示了一个典型的头-尾相互作用模式，包括主要的分子间EC 1：EC 4和EC2：EC 3相互作用的同型反式二聚体。一个子集的反式界面残基表现出异构体特异性的保护，这表明在识别特异性的作用。这些残基的突变，沿着与反式相互作用的伙伴残基，改变了Pcdh相互作用的特异性。总之，这些数据显示了Pcdh亚型之间的序列变异如何编码其不同的严格的嗜同性识别特异性，这是它们在神经回路组装中的关键作用所必需的。
Clustered protocadherin proteins (α-, β- and γ-Pcdhs) provide a high level of cell surface diversity to individual vertebrate neurons, engaging in highly specific homophilic interactions to mediate important roles in mammalian neural circuit development. How Pcdhs bind homophilically through their extracellular cadherin (EC) domains among dozens of highly similar isoforms has not been determined. Here we report crystal structures for extracellular regions from four mouse Pcdh isoforms (α4, α7, β6 and β8), revealing a canonical head-to-tail interaction mode for homophilic trans dimers comprising primary intermolecular EC1:EC4 and EC2:EC3 interactions. A subset of trans interface residues exhibit isoform-specific conservation, suggesting roles in recognition specificity. Mutation of these residues, along with trans-interacting partner residues, altered the specificities of Pcdh interactions. Together, these data show how sequence variation among Pcdh isoforms encodes their diverse strict homophilic recognition specificities, which are required for their key roles in neural circuit assembly.