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.
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