Molecular design principles underlying β-strand swapping in the adhesive dimerization of cadherins

Nat Struct Mol Biol. 2011 Jun;18(6):693-700. doi: 10.1038/nsmb.2051. Epub 2011 May 15.


Cell adhesion by classical cadherins is mediated by dimerization of their EC1 domains through the 'swapping' of N-terminal β-strands. We use molecular simulations, measurements of binding affinities and X-ray crystallography to provide a detailed picture of the structural and energetic factors that control the adhesive dimerization of cadherins. We show that strand swapping in EC1 is driven by conformational strain in cadherin monomers that arises from the anchoring of their short N-terminal strand at one end by the conserved Trp2 and at the other by ligation to Ca(2+) ions. We also demonstrate that a conserved proline-proline motif functions to avoid the formation of an overly tight interface where affinity differences between different cadherins, crucial at the cellular level, are lost. We use these findings to design site-directed mutations that transform a monomeric EC2-EC3 domain cadherin construct into a strand-swapped dimer.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cadherins / chemistry*
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Calcium / metabolism
  • Cations, Divalent / metabolism
  • Crystallography, X-Ray
  • Mice
  • Models, Chemical
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Protein Binding
  • Protein Conformation
  • Protein Multimerization*


  • Cadherins
  • Cations, Divalent
  • Mutant Proteins
  • Calcium