Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.603783
Title: The molecular mechanism of cadherin-mediated adhesion
Author: Harrison, O. J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2006
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Abstract:
My work examines the role of a conserved tryptophan residue, Trp2, in the adhesive domain of cadherins that has been shown to be essential for their adhesive function. Structural studies have shown Trp2 to be integrated into its own cadherin domain, integrated into the domain an opposing cadherin molecule, or freed from the domain and exposed to solvent. Until now, the physiological relevance of these structures has been controversial. Using conformation specific antibodies I show that Trp2 integrates into the domain fold of its own cadherin molecule in physiological conditions, but that this integration is not stable owing to structural constraints imposed by calcium binding to the cadherin. This raises the possibility that Trp2 could participate in intermolecular interactions during adhesion by inserting into opposing cadherins in what is referred to as the strand exchange model of cadherin adhesion. This model is tested directly by introducing cysteine substitutions into opposing cadherins such that disulphide bonds can form between them during adhesion only if they engage in strand exchange. The results provide clear evidence that strand exchange is central to adhesion by classical cadherins. Further results demonstrate that exchange of Trp2 in this way is stabilised by formation of a salt bridge. By disrupting this salt bridge with point mutations we find that if the tendency of Trp2 to integrate into its own domain and thus be unavailable for adhesion is inhibited, adhesion can be greatly enhanced. Our results thus define the mechanism of cadherin adhesion as a dynamic balance between the conflicting tendencies of Trp2 to engage in intramolecular and intermolecular interactions.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.603783  DOI: Not available
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