The spacing between the cell membranes at an anchoring junction is precisely defined and depends on the structure of the participating cadherin molecules. All the members of the superfamily, by definition, have an extracellular portion consisting of several copies of the extracellular cadherin (EC) domain. Homophilic binding occurs at the N-terminal tips of the cadherin molecules—the cadherin domains that lie furthest from the membrane. These terminal domains each form a knob and a nearby pocket, and the cadherin molecules protruding from opposite cell membranes bind by insertion of the knob of one domain into the pocket of the other (Figure 19–6A).
Each cadherin domain forms a more-or-less rigid unit, joined to the next cadherin domain by a hinge. Ca2+ ions bind to sites near each hinge and prevent it from flexing, so that the whole string of cadherin domains behaves as a rigid and slightly curved rod. When Ca2+ is removed, the hinges can flex, and the structure becomes floppy (Figure 19–6B). At the same time, the conformation at the N-terminus is thought to change slightly, weakening the binding affinity for the matching cadherin molecule on the opposite cell.
Unlike receptors for soluble signal molecules, which bind their specific ligand with high affinity, cadherins (and most other cell–cell adhesion proteins) typically bind to their partners with relatively low affinity. Strong attachments result from the formation of many such weak bonds in parallel. When binding to oppositely oriented partners on another cell, cadherin molecules are often clustered side-to-side with many other cadherin molecules on the same cell (Figure 19–6C). The strength of this junction is far greater than that of any individual intermolecular bond, and yet regulatory mechanisms can easily disassemble the junction by separating the molecules sequentially, just as two pieces of fabric can be joined strongly by Velcro and yet easily peeled apart from the sides. A similar “Velcro principle” also operates at cell–cell and cell–matrix adhesions formed by other types of transmembrane adhesion proteins.
Figure 19–4 The cadherin superfamily.
the diagram shows some of the diversity among cadherin superfamily members. these proteins all have extracellular portions containing multiple copies of the extracellular cadherin domain (green ovals). In the classical cadherins of vertebrates there are 5 of these domains, and in desmogleins and desmocollins there are  4 or 5, but some nonclassical cadherins have more than 30. the intracellular portions are more varied, reflecting interactions with a wide variety of intracellular ligands, including signaling molecules and adaptor proteins that connect the cadherin to the cytoskeleton. In some cases, such as t-cadherin, a transmembrane domain is not present and the protein is attached to the plasma membrane by a glycosylphosphatidylinositol (GpI) anchor. the differently colored motifs in Fat, Flamingo, and ret represent conserved domains that are also found in other protein families.
Figure 19–5 Homophilic versus heterophilic binding. Cadherins in general bind homophilically; some other cell adhesion molecules, discussed later, bind heterophilically.
38.5 nm hinge regions