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Classical cadherin molecules possess functional sites for adhesive recognition, calcium binding, membrane integration, cytoskeletal interactions and posttranslational modifications such as glycosylation, phosphorylation and proteolysis. All classic cadherins are contain a conserved cytoplasmic domain in the carboxyl terminus that interacts with the catenins characterized by Armadillo-repeats. The cytoplasmic domain has a serine-rich region that interacts with b-catenin. b-catenin then binds to a-catenin which connects the cadherin-catenin complex to the actin cytoskeleton. More recently, it was found that a different group of catenins binds to cytoplasmic domain including include p120 and d-catenin.

NMR structure of Ncad1

In 1995, Overduin determined the structure of the first domain of E-cadherin using NMR spectroscopy. Subsequently, the crystal structure of the first domain of N-cadherin (Ncad1) was solved. The fold consists of a seven-strand b-sheet (A, A', B,C,D,E,F,and G. A and A' parts are parts of the same strand), with the N and C termini located at opposite ends of the molecule. The segment connecting strands B and C adopts an apparently helical structure made of a succession of b-turn and b-like hydrogen bonds. This unique quasi-b-helix structure is characteristic of the cadherin fold.

Ecad12 Homodimer

The crystal structure of the E-cadherin fragment containing domains 1 and 2 (Ecad12) showed that calcium is central in E-cadherin dimer formation. Within the dimer, there are three Ca2+ ions bound per cadherin molecule. The residues that are involved in binding of three Ca2+ ions are located around the linker region between domain 1 and 2: Glu11, Glu69, Asp100, Gln101, Asn102, Asp103, Asp136, and Asn143. These Ca2+ binding sites were also found in the crystal structure of the N-cadherin fragment containing the two N terminus cadherin repeats (Ncad12). Single amino acid substitutions in the calcium binding sites can disrupt cell aggregation in vivo . Early biochemical and biophysical data suggested several explanations for this dependence, including rigidifying cadherin structure and conferring resistance to proteolysis.

Crystal structures of both Ecad12 and Ncad1 show parallel homodimer formation, however the dimer interfaces are different. The homodimer of Ncad1 does not depend on Ca2+ whereas Ecad12 requires Ca2+. In the crystal structure of the Ncad1, the Trp 2 side chain is intercalated into the hydrophobic core of the partner forming an intimate 'strand' dimer. This type of interface was not observed in a subseqeuent crystal structure of Ncad12. On the other hand, Ecad12 forms a weak homodimer mediated by calcium ions and water molecules with contacts that are mostly located in the linker region between the domains.

Possible lattice structure

Structural and biophysical studies on E-cadherin support a model in which parallel dimerization of cadherin molecules are mediated by Ca2+ ions. In this model, parallel dimerization is prerequisite to cell adhesion. Prior to calcium binding, the cadherin monomers are flexible at the linker region, so they can have many conformations. Upon calcium binding at the linker region, the cadherin molecule rigidifies, adopting a conformation where cadherins can dimerize loosely, as exemplified by the weakness of the Ecad12 dimer. The stability of a weak dimer would depend on the dimerization of adjacent cadherin molecules in a lattice structure. The lattice would form only if a critical concentration of cadherins on the cell surface is met. The dimerization step coupled with perhaps interactions in the cytoplasm or other cadherin repeats are required for the formation of an ordered lattice of cadherins. Finally, the cadherin lattice adheres in a calcium independent manner with another cadherin lattice formed at the opposite cell surface to achieve cadherin-mediated cell-cell adhesion.

Although an early study on electron microscopy imaging of extracellular cadherin constructs suggested that interactions between cadherin monomers are limited to the N-terminal tip of the molecule, there is increasing evidence that other extracellular parts of cadherins and/or the intracellular domain are involved in lateral clustering and ultimately cell adhesion. Using atom force microscopy, Sivasankar demonstrated that the extracellular domain of cadherin exhibits multiple adhesive contacts possibly involving other repeats in the molecule. In addition, the dimensions of the cadherin molecule suggest the likely involvement of other cadherin repeats in cell-cell adhesion. A single cadherin repeat spans ~45 angstroms and upon rigidification by calcium binding, the complete extracellular domain of cadherin spans ~240 angstroms. If the adhesion interface involves only the N terminal cadherin repeat, then the distance between opposite cells should be ~440 angstrom, however, the distance between the cell-cell distance is ~250-350 angstroms. Therefore, to conform to that constraint, there may be lateral interactions involving other cadherin repeats.

Thus, future structural work will be focused on elucidating the entire extracellular domain, as well as the more elusive cytoplasmic domain interacting with b-catenins. The structure of the b-catenin armadillo repeat reported by Huber and recently the structure of a-catenin reported by Pokutta will ultimately serve, in conjunction with the information available for cadherins, as a basis for understanding of cell-cell adhesion and various signaling and cell development events.