Alignment of cadherin N-terminal EC1 domains. The top three sequences are from type I classical cadherins, followed by four type II classical cadherin sequences. Desmocollin and desmoglein are desmosomal cadherins. Calcium binding resides are shaded yellow. Residues shown by x-ray crystallography of type I and type II cadherins to be involved in the dimer interface are shaded in grey. Additional residues, outlined in black, are involved in the more extensive type II interface that is postulated to confer extra rigidity to the corresponding dimer [25 **]. In this respect, desmosomal cadherins appear to be more similar to type I cadherins, suggesting that they maintain the flexible geometry seen in the corresponding dimeric structures [12].

Architecture of the intracellular plaque. (a) A tomographic slice through a desmosome from new-born mouse epidermis preserved by freeze-substitution and thin sectioning. (b) 3D rendering of components based on segmentation of the tomographic volume. Red planes correspond to the plasma membrane from opposing cells. The outer dense plaque (ODP) is shown in gold, extends ∼18.5 nm from the membrane and has very dense staining. The inner dense plaque (IDP) is shown in green, extends ∼37.5 nm from the ODP and consists of strand-like connections to the intermediate filaments (IF). Several ribosomes are shown in purple at the periphery of the junction. Although densities corresponding to cadherins are visible in the intercellular space, they have not been rendered in the 3D model. (c) Another tomographic section through new-born mouse epidermis. A desmosome appears to be forming (black arrow) with a low density of individual cadherin molecules visible in the intercellular gap and a light accumulation of material in the intracellular plaque. Another junction is visible with a smaller interacellular spacing (white arrow), which could be an adherens junction. In fact, adherens junctions are believed to have a role in directing desmosome assembly [52]. Individual densities are also visible protruding from the plasma membrane outside of junctions (black arrowhead) and could correspond to free cadherins. White arrowhead indicates ribosomes. Scale bars in (a) and (c) correspond to 5 nm.

Protein components of the desmosome. Individual components are superimposed on the grey-scale electron micrograph at the center of this figure. The membranes of opposing cells are shown as red lines with the distinctive mid-line indicated by the white arrow. White strands correspond to cadherin molecules, which are type I membrane proteins that directly mediate the intercellular bond. The intracellular plaque is segregated into two regions. The outer dense plaque is immediately adjacent to the membrane and comprises the intracellular tails of cadherins (white), plakoglobin (orange), plakophilin (yellow) and the N-terminal domain of desmoplakin (blue). The inner dense plaque comprises the rod domain and C-terminal domain of desmoplakin (blue), the latter of which associates with a network of intermediate filaments (green). X-ray crystal structures related to these various components are shown around the periphery of this figure at approximately the same scale. The cadherin trans dimer corresponds to the two-fold symmetric interaction seen in the x-ray crystal structure of the five extracellular domains of C-cadherin [12]. The ARM repeats of plakoglobin have been shown to interact with the intracellular tails of desmosomal cadherins and are represented here by the structure of the highly homologous β-catenin [27]; the orange spheres represent N- and C-terminal domains of unknown structure (∼100 residues each). The ARM repeats of plakophilin [35 **] are shown associated with an N-terminal domain of unknown structure (∼300 residues), which has been shown to interact with desmoplakin and many other components of the outer dense plaque. The central domain of desmoplakin is predicted to form a long coiled coil consisting of 889 residues and is shown here as three discontinuous lengths derived from the x-ray structure of tropomyosin. The C-terminal domain is characterized by three plakin repeat domains that bind intermediate filaments; the corresponding structures [43] have been packed arbitrarily within a sphere with a volume comparable to the entire 926-residue C-terminal domain. The N-terminal domain, which has been shown to interact with plakophilin and other components of the outer dense plaque, is depicted simply as a sphere of unknown structure. Scale bar corresponds to 3 nm.