CONSIDERATIONS ON THE FOLDING TOPOLOGY AND EVOLUTIONARY ORIGIN OF CADHERIN DOMAINS

Cell-cell adhesion in zonula adherens and desmosomal junctions is medi ated by cadherins, and recent crystal structures of the first domain f rom murine N-cadherin provide a plausible molecular basis for this adh esive action. A structure-based sequence analysis of this adhesive dom ain indicates that its fold is common to all extracellular cadherin do mains. The cadherin folding topology is also shown to be similar to im munoglobulin-like domains and to other Greek-key beta-sandwich structu res, as diverse as domains from plant cytochromes, bacterial cellulase s, and eukaryotic transcription factors. Sequence similarities between cadherins and these other molecules are very low, however, and intron patterns are also different. On balance, independent origins for a fa vorable folding topology seem more likely than evolutionary divergence from an ancestor common to cadherins and immunoglobulins.