STRUCTURE AND FUNCTION OF DESMOSOMAL TRANSMEMBRANE CORE AND PLAQUE MOLECULES

Desmosomes are intercellular junctions that function in cell-cell adhe sion and attachment of intermediate filaments (IF) to the cell surface . Desmogleins and desmocollins are the major components of the transme mbrane adhesion complex, whereas desmoplakins (DPs) are the most promi nent components of the cytoplasmic plaque. Based on sequence similarit y, desmogleins and desmocollins are related to the calcium-dependent h omophilic adhesion molecules known as cadherins. Like the classical ca dherins, the desmosomal cadherins contain four homologous extracellula r domains bearing putative calcium-binding sites, a single transmembra ne spanning domain, and a C-terminal cytoplasmic tail. Molecules in th e desmoglein subclass contain a unique C-terminal extension within whi ch is found a repeating motif that is predicted to form two P-strands and two turns. Stable cell lines expressing desmoglein 1 have been gen erated from normally non-adherent L cell fibroblasts, to study the con tribution of this cadherin to desmosomal adhesion. The predicted seque nce of desmoplakin (DP) I suggests it will form homodimers comprising a central alpha-helical coiled-coil rod and two globular end domains. The C-terminus contains three regions with significant homology, each of which is made up of a 38-residue motif also found in two other mole cules involved in organization of IF, bullous pemphigoid antigen and p lectin. Ectopically expressed polypeptides including the C-terminus of DP I specifically align with keratin and vimentin IF in cultured cell s, whereas those lacking this domain do not align with IF. The last 68 amino acids of DP are required for alignment along keratin but not vi mentin IF, and residues 48-68 from the C-terminal end are critical for this interaction. These results suggest that the C-terminus of DP pla ys a role in the attachment of IF to the desmosome and that a specific site is necessary for interaction with keratin IF. A sequence at the most N-terminal end of DP appears to be required for efficient incorpo ration into the desmosomal plaque. Interestingly, this region has not been reported to be present in the homologous bullous pemphigoid antig en or plectin molecules and may represent a desmosomal targeting seque nce.