Functional cis-heterodimers of N- and R-cadherins

Classical cadherins form parallel cis-dimers that emanate from a single cel l surface. It is thought that the cis-dimeric form is active in cell-cell a dhesion, whereas cadherin monomers are likely to be inactive. Currently, ci s-dimers have been shown to exist only between cadherins of the same type. Here, we show the specific formation of cis-heterodimers between N- and R-c adherins. E-cadherin cannot participate in these complexes. Cells coexpress ing N- and R-cadherins show hemophilic adhesion in which these proteins coa ssociate at cell-cell interfaces. We performed site-directed mutagenesis st udies, the results of which sup-port the strand dimer model for cis-dimeriz ation. Furthermore, we show that when N- and R-cadherins are coexpressed in neurons in vitro, the two cadherins colocalize at certain neural synapses, implying biological relevance for these complexes. The present study provi des a novel paradigm for cadherin interaction whereby selective cis-heterod imer formation may generate new functional units to mediate cell-cell adhes ion.