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

Combinatorial homophilic interaction between γ-protocadherin multimers greatly expands the molecular diversity of cell adhesion
Dietmar Schreiner and Joshua A. Weiner1
+ Author Affiliations

Department of Biology, University of Iowa, Iowa City, IA 52242
Edited* by Joshua R. Sanes, Harvard University, Cambridge, MA, and approved June 30, 2010 (received for review April 6, 2010)

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 Ca2+-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 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 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.

cadherincalcium-dependentsynaptogenesisrecognitiontrafficking

Footnotes
1To whom correspondence should be addressed. E-mail: joshua-weiner@uiowa.edu. Author contributions: D.S. and J.A.W. designed research; D.S. performed research; D.S. contributed new reagents/analytic tools; D.S. and J.A.W. analyzed data; and D.S. and J.A.W. wrote the paper.
The authors declare no conflict of interest.
↵*This Direct Submission article had a prearranged editor.
This article contains supporting information online at
www.pnas.org/lookup/suppl/doi:10.1073/pnas.1004526107/-/DCSupplemental.

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