Dimerization of Cadherin-11 involves multi-site coupled unfolding and strand swapping.

Cadherin extracellular domain 1 (EC1) mediates homophilic dimerization in adherens junctions. Conserved Trp2 and Trp4 residues in type II cadherins anchor the EC1 A strand intermolecularly in strand-swapped dimers. Herein, NMR spectroscopy is used to elucidate the roles of Trp2 and Trp4 in Cadherin-11 dimerization. The monomeric state, with the A strand and Trp side chains packed intramolecularly, is in equilibrium with sparsely populated partially and fully A-strand-exposed states, in which Trp2 (and Trp4, respectively) side-chain packing is disrupted. Exchange kinetics between the major state and the partially (fully) A-strand-exposed state is slow-intermediate (intermediate-fast). A separate very fast process exchanges ordered and random-coil BC-loop conformations with populations dependent on A-strand exposure and dimerization status. In addition, very slow processes connect the folded A-strand-exposed conformation to partially unfolded states, which may represent additional domain-swapping intermediates. The dimerization mechanism of type II cadherins is revealed as coupled folding and strand swapping.