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

Structure. 2021 Oct 7;29(10):1105-1115.e6. doi: 10.1016/j.str.2021.06.006. Epub 2021 Jun 23.

Abstract

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.

Keywords: CEST; CPMG relaxation dispersion; adherens junctions; cell adhesion; chemical exchange; domain-swapping; high-pressure NMR; protein dynamics and kinetics; type II cadherin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Cadherins / chemistry*
  • Cadherins / genetics
  • Cadherins / metabolism
  • Mice
  • Protein Conformation, alpha-Helical
  • Protein Domains
  • Protein Folding
  • Protein Multimerization*

Substances

  • Cadherins
  • osteoblast cadherin