期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：33
页码：14893-14898
DOI：10.1073/pnas.1004526107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
