Combinatorial homophilic interaction between γ-protocadherin multimers greatly expands the molecular diversity of cell adhesion

Abstract

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 γ-Pcdh family, which have been shown to be critical for the control of synaptogenesis and neuronal survival. We show that γ-Pcdh isoforms engage in trans interactions that are strictly homophilic. In contrast to classical cadherins, γ-Pcdh interactions are only partially Ca 2+ -dependent, and their specificity is mediated through the second and third extracellular cadherin (EC) domains (EC2 and EC3), rather than through EC1. The γ-Pcdhs also interact both covalently and noncovalently in the cis-orientation to form multimers both in vitro and in vivo. In contrast to γ-Pcdh trans interactions, cis interactions are highly promiscuous, with no isoform specificity. We present data supporting a model in which γ-Pcdh cistetramers represent the unit of their adhesive trans interactions. Unrestricted tetramerization in cis, coupled with strictly homophilic interactions in trans, predicts that the 22 γ-Pcdhs could form 234,256 distinct adhesive interfaces. Given the demonstrated role of the γ-Pcdhs in synaptogenesis, our data have important implications for the molecular control of neuronal specificity.cadherin | calcium-dependent | synaptogenesis | recognition | trafficking

Clustered protocadherins

“…Like classical cadherins, members of the Pcdh family were also shown to mediate cell-cell adhesion in cell-based assays (Obata et al, 1995;Frank et al, 2005;Reiss et al, 2006), and multiple Pcdhg proteins were shown to engage in homophilic trans-interactions (Fernández-Monreal et al, 2009;Schreiner and Weiner, 2010). Unlike classical cadherins, however, the binding specificity of Pcdhs is not determined by the EC1 domain, but instead is mediated by the EC2 and EC3 domains (Schreiner and Weiner, 2010), which are highly divergent between distinct Pcdh isoforms (Wu, 2005). It has been proposed that cis-tetramers, rather than monomers (as in the cases of classical cadherins or Dscams), represent the unit of Pcdh homophilc trans-interactions (Schreiner and Weiner, 2010).…”

“…Classical cadherins mediate cell-cell adhesion via transhomodimerization between their extracellular domains extended from apposing cell membranes, and they assemble intercellular adherens junctions through cis-clustering (Brasch et al, 2012). Like classical cadherins, members of the Pcdh family were also shown to mediate cell-cell adhesion in cell-based assays (Obata et al, 1995; Frank et al, 2005;Reiss et al, 2006), and multiple Pcdhg proteins were shown to engage in homophilic trans-interactions (Fernández-Monreal et al, 2009;Schreiner and Weiner, 2010). Unlike classical cadherins, however, the binding specificity of Pcdhs is not determined by the EC1 domain, but instead is mediated by the EC2 and EC3 domains (Schreiner and Weiner, 2010), which are highly divergent between distinct Pcdh isoforms (Wu, 2005).…”

Protocadherin a gene cluster is required for myelination and oligodendrocyte development

“…)。多样性的 Pcdh 分子通过同嗜或异嗜结合的 方式特异性地表达于神经元的细胞膜上, 并影响神 经 细 胞 间 的 特 异 性 链 接 (Weiner et al 2005;Schreiner & Weiner, 2010;Takeichi, 2007)。 Pcdh 分子 还可以通过其胞内结构域与其它胞内蛋白相互作用, 进而影响神经细胞的存活 (Emond & Jontes, 2008;Fernández-Monreal et al, 2009, Han et al, 2010 …”

Dendritic self-avoidance: protocadherins have it covered

“…Different isoforms are expressed in stochastic and combinatorial patterns in individual neurons. Pcdh isoforms interact to form hetero-tetramers and show isoform-specific homophilic binding [12]. As a result, many thousands of distinct binding specificities can be generated from the Pcdh locus.…”