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First published online 25 January 2005
doi: 10.1242/jcs.01665

Journal of Cell Science 118, 711-721 (2005)
Published by The Company of Biologists 2005
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Research Article

The mechanism of cell adhesion by classical cadherins: the role of domain 1

Oliver J. Harrison1, Elaine M. Corps1, Torunn Berge2,* and Peter J. Kilshaw1,{ddagger}

1 The Babraham Institute, Babraham, Cambridge, CB2 4AT, UK
2 Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QJ, UK

{ddagger} Author for correspondence (e-mail: peter.kilshaw{at}bbsrc.ac.uk)

Accepted 24 November 2004

The mechanism by which classical cadherins mediate cell adhesion and, in particular, the roles played by calcium and Trp2, the second amino acid in the N-terminal domain, have long been controversial. We have used antibodies to investigate the respective contributions of Trp2 and calcium to the stability of the N-terminal domain of N-cadherin. Using a peptide antibody to the ßB strand in domain 1, which detects a disordered structure, we show that both Trp2 and calcium play crucial parts in regulating stability of the domain. The epitope for another antibody, mAb GC4, has been mapped to the base of domain 1. Binding of GC4 to this epitope was shown to depend on intramolecular `docking' of Trp2 into the domain 1 structure. Using this property, we provide evidence that calcium regulates a dynamic equilibrium between docked and undocked Trp2. Finally, a novel technique has been developed to test whether Trp2 cross-intercalation between cadherin molecules from adjacent cells (strand exchange) is central to cadherin-mediated cell adhesion. Guided by crystal structures showing strand exchange, we have introduced single cysteine point mutations into N-cadherin domain 1 in such a way that a disulphide bond will form between opposing N-cadherin molecules during cell adhesion if strand exchange occurs. The bond requires complementary cysteines to be precisely juxtaposed according to the strand exchange model. Our results demonstrate that the disulphide bond forms as predicted. This provides compelling evidence that strand exchange is indeed a primary event in cell adhesion by classical cadherins.

Key words: Cadherin, Adhesion, Strand exchange




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