Cadherins are thought to be the primary mediators of adhesion between the cells of vertebrate animals, and also function in cell adhesion in many invertebrates.   The expression of numerous cadherins during development is highly regulated, and the precise pattern of cadherin expression plays a pivotal role in the morphogenesis of tissues and organs.   Furthermore, cadherins are important in the continued maintenance of tissue structure and integrity, for example loss of cadherin expression appears to be highly correlated with the invasiveness of some types of tumors.   Cell adhesion mediated by cadherins is thought to be homotypic.  That is to say that a cell expressing type X cadherin will associate with another cell expressing cadherin X.   Cadherin adhesion is also dependent on the presence of millimolar calcium ion concentrations, as are found in the extracellular milieu.

    The cadherin protein superfamily, defined as proteins containing a cadherin-like domain, can be divided into several sub-groups.   These include the classical (type I) cadherins, which mediate adhesion at adherens junctions; the highly-related type II cadherins; the desmosomal cadherins found in desmosome junctions; protocadherins, expressed only in the nervous system; and atypical cadherin-like domain containing proteins.   Members of all but the atypical group have been shown to play a role in intercellular adhesion.

    Classical, type II, and desmosomal cadherins share a common domain organization:  Each comprises five tandem extracellular cadherin domains, a single transmembrane segment, and a highly conserved cytoplasmic domain.   The cytoplasmic domains of the classical cadherins, thought to interact with the actin cytoskeleton through specific adaptor proteins, are distinct from those of desmosomal cadherins, which attach to the intermediate filament system.   The protocadherins, which may take part in defining the specificity of synaptic connections between neurons, are encoded in a novel gene locus containing fifty-two single-exon "variable" ectodomain regions, and at least two cytoplasmic domain "constant" regions in humans.   The mature proteins derive from combining the extracellular and cytoplasmic regions through a highly regulated mRNA splicing pathway. Protocadherins contain six tandem cadherin-like domains in the extracellular segment, and each of the known cytoplasmic domains is unrelated to other known proteins.

    High-resolution structural studies have shown that the sequence repeats of cadherin extracellular segments fold into domains with an immunoglobulin-like topology.   The connections between these domains are rigidified by the ligation of three Ca²⁺ ions by conserved residues at the "bottom" of domain n, the "top" of domain n+1, and the linker segment between them.   Despite the information gained from these structural studies, the central question of cadherin molecular function has remained: What is the atomic-level basis of cadherin function in adhesion?   What intermolecular interface(s) provides the attachment point between cells, and what are the determinants of adhesive specificity?


    Several intermolecular interfaces have been identified in cadherin crystal structures, and others have been suggested based on mutagenesis data, peptide inhibition studies, and analogy to binding sites in similarly folded immunoglobulin-like domain.   One of these interfaces, observed in the first set of cadherin domain crystal structures, is comprised of a conserved tryptophan side chain (from Trp 2) that intercalates into a conserved hydrophobic pocket in a partner molecule.   This interface, called the "strand dimer" because it involves the symmetrical exchange of N-terminal -strands between EC1 domain protomers, has been shown to be essential for cadherin adhesion by site-directed mutagenesis of both Trp 2 and its acceptor pocket.   However, the orientation of protomers in the initial strand dimer structures led to the suggestion that its function would likely involve cis or same-cell interactions rather than trans adhesion between juxtaposing cells.


    In our recent paper, we show that, in the crystal structure of the C-cadherin ectodomain, the strand dimer appears in an orientation clearly poised for adhesion between cadherins presented from adjacent cells.   The dependence of cadherin-based cell adhesion on the fidelity of the elements of this interface suggests that the strand dimer is critical for the adhesive function of the classical cadherins.   Although the functional data cannot definitively distinguish between a role for this interface in cis or trans interactions, our structure suggests that it may directly participate in the adhesive interaction.   Furthermore, the simple two-fold symmetry of this interface suggests a rationale for the homophilic specificity observed for cadherins generally, and reveals the molecular regions of the likely determinants of cadherin specificity.

Publications

Curr Opin Struct Biol
2003;13:690-698
Cadherin-mediated cell-cell adhesion: sticking together as a family.
Patel SD, Chen CP, Bahna F, Honig B, Shapiro L   
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