Dsg1 is a 165-kDa glycoprotein component of suprabasal epidermal desmosomes and the prototype of a subset of the cadherin superfamily of cell-cell adhesion proteins known as desmogleins. The adhesive function of classical cadherins is known to be dependent upon their association with cytoplasmic components called catenins. In the case of desmogleins, a single interaction has been described with a protein called plakoglobin that is found in desmosomal plaques, adherens junctions, and the cytosol. Several proteins with homology to plakoglobin have been described that regulate junction assembly and implement morphoregulatory signals. To address the functional significance of plakoglobin-desmoglein interaction, we have mapped the sequences of Dsg1 that are crucial for this association by using blot overlay techniques. By examining the binding of plakoglobin to a deletion series of the Dsg1 cytoplasmic domain expressed as fusion proteins, we have defined a 19-amino acid sequence that is important for association. This region of Dsg1 sequence shows significant similarity to the catenin-binding domain of classical cadherins, suggesting a common mechanism for the association of plakoglobin with desmosomes and adherens junctions.