Combinatorial homophilic interaction between γ-protocadherin multimers greatly expands the molecular diversity of cell adhesion
Combinatorial homophilic interaction between γ-protocadherin multimers greatly expands the molecular diversity of cell adhesion
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DOI：
10.1073/pnas.1004526107
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发表时间：
2010-08-17
影响因子：
11.1
通讯作者：
Weiner, Joshua A.
中科院分区：
文献类型：
--
作者：
Schreiner, Dietmar;Weiner, Joshua A.
神经元之间相互作用的特异性被认为是由不同的细胞粘附分子介导的，包括钙粘蛋白超家族的成员。尽管经典的钙粘蛋白粘附机制已被广泛研究，但对相关的原钙粘蛋白（Pcdhs）知之甚少，它们共同构成了超家族的大部分。在这里，我们使用定量细胞聚集试验和生化分析，以表征顺式和反式之间的相互作用的22个成员的γ-Pcdh家族，这已被证明是至关重要的控制突触和神经元的生存。我们发现，γ-Pcdh亚型从事反式相互作用，是严格的同性恋。与经典钙粘蛋白相反，γ-Pcdh相互作用仅部分依赖于Ca 2+，并且其特异性通过第二和第三胞外钙粘蛋白（EC）结构域（EC 2和EC 3）介导，而不是通过EC 1介导。γ-Pcdhs还以顺式取向共价和非共价相互作用，以在体外和体内形成多聚体。与γ-Pcdh反式相互作用相反，顺式相互作用是高度混杂的，没有同种型特异性。我们目前的数据支持一个模型，其中γ-Pcdh顺式四聚体代表他们的粘合剂反式相互作用的单位。顺式的不受限制的四聚体，加上反式的严格亲同性相互作用，预测22个γ-Pcdhs可以形成234，256个不同的粘合界面。鉴于γ-Pcdhs在突触发生中的作用，我们的数据对神经元特异性的分子控制具有重要意义。
The specificity of interactions between neurons is believed to be mediated by diverse cell adhesion molecules, including members of the cadherin superfamily. Whereas mechanisms of classical cadherin adhesion have been studied extensively, much less is known about the related protocadherins (Pcdhs), which together make up the majority of the superfamily. Here we use quantitative cell aggregation assays and biochemical analyses to characterize cis and trans interactions among the 22-member gamma-Pcdh family, which have been shown to be critical for the control of synaptogenesis and neuronal survival. We show that gamma-Pcdh isoforms engage in trans interactions that are strictly homophilic. In contrast to classical cadherins, gamma-Pcdh interactions are only partially Ca2+-dependent, and their specificity is mediated through the second and third extracellular cadherin (EC) domains (EC2 and EC3), rather than through EC1. The gamma-Pcdhs also interact both covalently and noncovalently in the cis-orientation to form multimers both in vitro and in vivo. In contrast to gamma-Pcdh trans interactions, cis interactions are highly promiscuous, with no isoform specificity. We present data supporting a model in which gamma-Pcdh cis-tetramers represent the unit of their adhesive trans interactions. Unrestricted tetramerization in cis, coupled with strictly homophilic interactions in trans, predicts that the 22 gamma-Pcdhs could form 234,256 distinct adhesive interfaces. Given the demonstrated role of the gamma-Pcdhs in synaptogenesis, our data have important implications for the molecular control of neuronal specificity.