Depletion of Ca(2+) ions from epithelial cell cultures has been shown to result in the rapid destruction of intercellular junctions. To understand the mechanism of this effect we have examined how removal of calcium ions from the culture medium of A-431 epithelial cells affects complexes incorporating the cell-cell adhesive receptors, E-cadherin, desmoglein or desmocollin. Sedimentation and biochemical analysis demonstrated that calcium removal triggers a rapid formation of a novel type of complex formed via direct lateral E-cadherin-desmoglein, E-cadherin-desmocollin and desmoglein-desmocollin dimerization of the extracellular cadherin regions. Replacement of Trp(156) and Val(157) of E-cadherin, that has been shown to abolish lateral and adhesive E-cadherin homodimerization in standard cultures, did not influence the formation of these 'calcium-sensitive' complexes. Furthermore, experiments with this mutant revealed that EGTA induced lateral Trp(156)/Val(157)-independent homodimerization of E-cadherin. Deletion mutagenesis of E-cadherin showed that these complexes are mediated by at least two extracellular cadherin domains, EC3 and EC4. Notably, protein kinase inhibitor H-7 which confers EGTA-independence of the adhesive E-cadherin complexes does not block this association. We propose that this novel type of intercadherin interaction is involved in the assembly of adherens junctions and their disassembly in low-calcium medium.