To investigate the possible biological function of the lateral ''stran
d dimer'' observed in crystal structures of a D1 domain extracellular
fragment from N-cadherin, we have undertaken site-directed mutagenesis
studies of this molecule. Mutation of most residues important in the
strand dimer interface abolish the ability of N-cadherin to mediate ce
ll adhesion. Mutation of an analogous central residue (Trp-2) in E-cad
herin also abrogates the adhesive capacity of that molecule. We also d
etermined the crystal structure of a Ca2+-complexed two-domain fragmen
t from N-cadherin. This structure, like its E-cadherin counterpart, do
es not adopt the strand dimer conformation. This suggests the possibil
ity that classical cadherins might stably exist in both dimeric and mo
nomeric forms. Data from several laboratories imply that:lateral dimer
ization or clustering of cadherins may increase their adhesivity. We s
uggest the possibility that the strand dimer may play a role in this a
ctivation.