Regulation of Homotypic Cell-Cell Adhesion

Cadherins are a family of evolutionarily conserved calcium-dependent single-pass transmembrane proteins characterized by the presence of an N-terminal ectodomain composed of tandem extracellular cadherin (EC) repeats that engage in extracellular interactions mediating cell-cell adhesion through dimerization, and a C-terminal cytoplasmic tail that interacts with catenins and links extracellular adhesion to the cytoskeleton. Based on their sequence similarity, cadherins can be grouped into type I classical cadherins, type II classical cadherins, clustered and non-clustered protocadherins, 7D cadherins, and CELSR cadherins; CDH13 and CDH26 have not been grouped so far. Type I and II classical cadherins are comprised of five extracellular cadherin (EC) repeats in their ectodomains. The first, membrane distal cadherin repeat (EC1) of type I classical cadherins possesses a conserved tryptophan residue at position 2, while the EC1 of type II classical cadherins has two conserved tryptophan residues, at positions 2 and 4. The conserved tryptophan residues are involved in dimerization. 7D cadherins have 7 cadherin repeats in their ectodomains and a conserved tryptophan residue in the third cadherin repeat. CELSR cadherins possess 6-9 cadherin repeats in their ectodomains and no conserved tryptophan residues. Calcium ions bind to cadherins at conserved sites in between consecutive EC repeats, commonly each site binding three calcium ions (Ca2+), and plays an important role in formation of strand-swapped trans dimers in classical cadherins, and protein rigidity in others. For review, refer to Brasch et al. 2012, Gul et al. 2017.