Structure Of Cadherins And Binding Interactions

Cadherins mediate calcium dependent, mostly homophilic adhesion. They were first identified in vertebrates, but the family is evolutionarily conserved and members can be found in echinoderms, arthropods, and chordates. Between phyla, there is substantial structural diversity, but cadherins have in common a cadherin domain—a —110 amino acid sequence that is usually one of several tandem repeats separated by a calcium-binding domain. Current estimates indicate that the cadherin superfamily has as many as 300 members that can be parsed into several subfamilies6 (Figure 5.1). By far the most is known about classic cadherins, which in vertebrates have five cadherin domains, but in nonchordates can have up to 15 (e.g., DN-cadherin in Drosophila). Their highly homologous intracellular domains bind strongly to the actin cytoskeleton via the catenin proteins: cadherins bind directly to armadillo repeat-containing proteins, 6 or y catenin, which bind in turn to the unrelated but similarly named a-catenin. Alpha-catenin binds to F-actin directly or indirectly via a-actinin. Classic cadherins and protocadherins (see Chapter 9) are the only cadherins that have been localized to synapses thus far.

Classic cadherins (usually referred to simply as "cadherins") mediate strong adhesion at junctions like adherens junctions or central nervous system (CNS) synapses but can also engage in weaker, nonjunctional adhesion such as that mediating neurite extension. A single cadherin extending from the plasma membrane of one cell engages its partner in trans in an interaction that is specified by the first cadherin domain, and requires at least the first two cadherin domains for adhesion7-9. The adhesive force generated by a single binding interaction in trans would be expected to be weak but could be important for traction during neurite extension. Within the plane of the plasma membrane, cadherins can also form cis-dimers with one another, and crystal structures of the ^-cadherin N-terminal EC1 domain support that a series of cis-dimerized cadherins could engage similarly dimerized cadherins in trans, forming an "adhesion zipper"7. This would be expected to confer very strong adhesion, and consistent with this idea, many junctional cadherins are resistant to trypsin digestion10. More recent work on the crystal structure of the entire extracellular domain of Xenopus C-cadherin suggests that the cis- and trans-binding interfaces may be shared and therefore must alternate binding with one another11. Thus, while it is not clear whether cis dimers form in vivo, a great deal of experimental evidence supports that cis-clustering augments trans adhesion. Cis interactions are modulated by proteins binding to the juxtamembrane domain: armadillo repeat-containing proteins p120 catenin and 8-catenin/NPRAP, and presenilin-1 which also participates in the e-cleavage of cadherins, a process that releases a C-terminal cadherin fragment into the cytosol12,13 (Figure 5.2).

Figure 5.1. Cadherins in the Nervous System. All have cadherin-type extracellular repeats. Data are repeats. Data are taken from refs 6,18,68. Abbreviations: CNR: cadherin-related neuronal receptor, GPI: glycosylphosphatidylinositol, RET: rearranged during transfection.

Most of the data on cadherin actions and the consequences of cadherin binding and signaling arise from experiments using the expression of cadherin mutant proteins or peptides mimicking key domains. Traditional genetic ablation has been less successful because many cadherins are essential for early stages stages of embryonic development prior to brain development, and experiments

Classic Cadherin intracellular and transmembrane signaling partners

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