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First published online 23 August 2005
doi: 10.1242/jcs.02539

This Article Figures Only Full Text Full Text (PDF) An erratum has been published All Versions of this Article: jcs.02539v1 118/18/4123    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Harrison, O. J. Articles by Kilshaw, P. J. Search for Related Content PubMed PubMed Citation Articles by Harrison, O. J. Articles by Kilshaw, P. J.

Cadherin adhesion depends on a salt bridge at the N-terminus

The Babraham Institute, Babraham, Cambridge, CB2 4AT, UK

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

Accepted 8 June 2005

There is now considerable evidence that cell adhesion by cadherins requires a strand exchange process in which the second amino acid at the N-terminus of the cadherin molecule, Trp2, docks into a hydrophobic pocket in the domain fold of the opposing cadherin. Here we show that strand exchange depends on a salt bridge formed between the N-terminal amino group of one cadherin molecule and the acidic side chain of Glu89 of the other. Prevention of this bond in N-cadherin by introducing the mutation Glu89Ala or by extending the N-terminus with additional amino acids strongly inhibited strand exchange. But when the two modifications were present in opposing cadherin molecules respectively, they acted in a complementary manner, lowering activation energy for strand exchange and greatly increasing the strength of the adhesive interaction. N-cadherin that retained an uncleaved prodomain or lacked Trp2 adhered strongly to the Glu89Ala mutant but not to wild-type molecules. Similarly, N-cadherin in which the hydrophobic acceptor pocket was blocked by an isoleucine side chain adhered to a partner that had an extended N-terminus. We explain these results in terms of the free energy changes that accompany strand exchange. Our findings provide new insight into the mechanism of adhesion and demonstrate the feasibility of greatly increasing cadherin affinity.

Key words: Cadherin, Salt bridge, Strand exchange, Tryptophan, N-terminus

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