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Title: Conformational studies of the domains and subunits of the high affinity IgE receptor by NMR and molecular modelling
Author: Zloh, Mire
ISNI:       0000 0001 3578 021X
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1998
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The sequence of the high affinity integral membrane receptor for immunoglobulin E, designated as FcԑRI, led to the proposal that it was an αβγ2 with seven transmembrane helices. The latter were connected by three loop peptides. FcԑRI had five cytoplasmic and one extracellular domain peptides. Except for the seven transmembrane helices most of these peptides were synthesized and their solution structure determined, whole or in part, by a combination of circular dichroism, Fourier transform infrared and multidimensional nuclear magnetic resonance spectroscopy. This experimentally-derived structural database then served as a basis for calculating the structures of subunits, especially the β-subunit of FcԑRI. To improve these determinations of the 3D structure, the arrangement of the transmembrane helices of the FcԑRI was studied using molecular modelling. Specifically, protein docking methods were used to study the interaction between all transmembrane helices of the FcԑRI and to establish the favourable helix surfaces for helix - helix contacts. This objective procedure led to the proposal that the transmembrane domain of the β-subunit consisted of a four helix bundle. Further information was needed to determine the 3D structure of the receptor and its subunits, specifically which helix surfaces favoured hydrophobic interactions with membrane lipids. Molecular mechanics was used to predict the relative lipid - transmembrane helix interacting surfaces. The interaction of dodecane and palmitic fatty acid with transmembrane helices led to mapping of the relative hydrophobic surfaces on these helices. This type of experiment successfully predicted the lipid-helix interaction surfaces which were in agreement with those found in the crystal structure of the Bacteriorhodopsin. It fully supported mapping of the hydrophobic surfaces and fatty acid interaction sites of all six different transmembrane helices of the IgE receptor. By experimentally elucidating the conformational components of domain peptides within the FcԑRI, it has therefore been possible to have an improved understanding of the structural interactions between receptor peptides, and between receptor peptides and lipids, and to model the conformation of the receptor subunits. The final 3D structures of the β-subunit were calculated by molecular dynamics using: a) NMR-based loop peptide structure; b) calculated helix-helix interactions; and c) mapping of lipid-helix interactions. The proposed structure of the β-subunit had the repeated conformational motif (transmembrane helix - turn - loop helix - bend - transmembrane helix).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Immunoglobulin E; Domain peptides