Dynamic properties of a type II cadherin adhesive domain: Implications for the mechanism of strand-swapping of classical cadherins

Cadherin-mediated cell adhesion is achieved through dinnerization of cadherin N-terminal extracellular (EC1) domains presented from apposed cells. The dinner state is formed by exchange of N-terminal 0 strands and insertion of conserved tryptophan indole side chains from one monomer into hydrophobic acceptor pockets of the partner molecule. The present work characterizes individual monomer and dimer states and the monomer-dimer equilibrium of the mouse Type 11 cadherin-8 EC1 domain using NIVIR spectroscopy. Limited picosecond-to-nanosecond timescale dynamics of the tryptophan indole moieties for both monomer and climer states are consistent with well-ordered packing of the N-terminal 0 strands intramolecularly and intermolecularly, respectively. However, pronounced microsecond-to-millisecond timescale dynamics of the side chains are observed for the monomer but not the dinner state, suggesting that monomers transiently sample configurations in which the indole moieties are exposed. The results suggest possible kinetic mechanisms for EC1 climerization.