Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.603613
Title: Folding and evolution of the immunoglobulin-like superfold
Author: Hamill, S. J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2000
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Abstract:
In this study, the structure, folding and stability of a number of proteins with the Ig-like fold are compared. This 'fold approach' is a new direction in the experimental study of the folding proteins with similar 3D structures but no sequence homology. Two evolutionary distinct superfamilies with the Greek key immunoglobulin-like (Ig-like) fold are considered: the immunoglobulins (Igs) and fibronectin type IIIs (fnIIIs). Part I focuses on the third fnIII domain of human tenascin, TNfm3. This module is 90 amino acids in length, has no disulphides, bound ions, cofactors, or cis prolines. Part II focuses on comparative studies of two other Ig-like proteins, rat CD2 domain 1 (CD2d1) and Ig18' of C. elegans twitchin (TWIg18'). Comparison of the folding of these proteins and several others, shows a distinct correlation between stability and folding rate. This trend is unique amongst protein families characterised to date, and implies that the stability of regions of conserved structure drives the folding reaction. Structural alignment reveals that the strongest bioinformatic signal, in terms of residue identity, is the tyrosine coroner motif that is found at the same position in each protein and is found ubiquitously and exclusively in Greek key proteins. Comparative protein engineering shows that the tyrosine corner is not a kinetic signal, but one for the structural stability, perhaps reflecting an evolutionary 'cul-de-sac'. Results from parts I and II are then drawn together to produce a model for the folding of Ig-like proteins. The common core of Ig-like domains consists of strands B, C, E and F, which form a double 'β-zipper' by the intercalculation of strands B-C and E-F. The stability of BCEF drives the folding of Ig-like proteins. Regions that also fold early may do so due to topological restriction. The BCEF unit is efficiently packed and the stability conferred from this is probably central to the evolutionary favourability of Greek key proteins.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.603613  DOI: Not available
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