Type II classical cadherins are comprised of five extracellular cadherin (EC) repeats in their ectodomain. The first cadherin repeat (EC1) of type II classical cadherins has two conserved tryptophan residues, at positions 2 and 4. The conserved tryptophan residues are critical for dimerization. Trans dimerization of classical cadherins occurs through a unique mechanism, called 'strand swapping', where one set of interactions in two monomers is replaced with an equivalent set of interactions in a dimer, through exchange of an N-terminal beta-strand facilitating docking of the Trp residues into a hydrophobic receptor pocket of the binding partner. This strand-swapping mechanism is aided by an intermediate non-swapped dimer, called X dimer, in accordance with the induced fit model. Type II classical cadherins include CDH5 (cadherin-5, also known as VE-cadherin, an atypical type II cadherin), CDH6 (cadherin-6, also known as K-cadherin), CDH7 (cadherin-7), CDH8 (cadherin-8), CDH9 (cadherin-9, also known as T1-cadherin), CDH10 (cadherin-10, also known as T2-cadherin), CDH11 (cadherin-11, also known as OB-cadherin), CDH12 (cadherin-12, also known as N-cadherin 2), CDH18 (cadherin-18), CDH19 (cadherin-19), CDH20 (cadherin-20), CDH22 (cadherin-22), and CDH24 (cadherin-24). For review, refer to Brasch et al. 2012, Gul et al. 2017.

Type II classical cadherins are predominantly expressed in the nervous system where they govern formation of neuronal circuits (e.g. cold perception, motor neuron bundling). In addition to homotypic dimer formation, type II classical cadherins form heterotypic dimers with other type II classical cadherins and can be divided into three specificity subgroups based on their binding preferences. The specificity subgroups correspond to the branches of the phylogenetic tree where binding between members has been retained. The first specificity subgroup includes CDH8 and CDH11, and likely CDH24, the second specificity subgroup includes CDH6, CDH9 and CDH10, and the third specificity subgroup includes CDH7, CDH12, CDH18, CDH20 and CDH22. The CDH8, CDH11, and CDH24 group does not bind to the others, while binding interactions are found within the other branches of the phylogenetic tree. Divergent type II cadherin CDH5 and CDH19 could not be placed in these specificity subgroups (Brasch et al. 2018).