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Title: Unravelling the interaction of the human IgG subclasses with their ligands using biophysical methods
Author: Hui, Gar Kay
ISNI:       0000 0004 7965 0662
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Antibodies are responsible for binding to antigens through their Fab arms and eliciting an immune response by binding to Fcγ receptors (FcγR). IgG4 is associated with IgG4-related disease. Human IgG in blood consists of four subclasses (IgG1, IgG2, IgG3 and IgG4). In order to identify their solution structures, monoclonal IgG1 and IgG4 and myeloma IgG2 were studied using analytical ultracentrifugation (AUC) and small-angle X-ray and neutron scattering (SAXS, SANS), followed by atomistic modelling using molecular dynamics and Monte Carlo methods. The three IgG subclasses exhibit variable conformations and flexibility, reflecting their function. FcγRI (CD64) is the sole high-affinity human IgG receptor. Its crystal structure showed that its three domains D1, D2 and D3 form a compact "seahorse" shape. To identify its solution structure, AUC and SAXS data and their modelling showed that FcγRI is more elongated than its crystal structure, in which the D1 and D2 domains were no longer in contact with each other, and the D3 domain showed flexibility. The solution structures of the IgG1 and IgG4 complexes with FcγRI were determined by AUC, SAXS and SANS. These showed a 1:1 binding stoichiometry. Their atomistic modelling showed that the Fc region in IgG1/IgG4 accommodates one FcγRI asymmetrically, and the two Fab arms were displaced to enable FcγRI binding. The modelling showed that the bound FcγRI changed conformation back into a compact "seahorse" where D1 is folded back against the D2 domain. Here, the solution structure of full-length IgG with FcγRI resembled the crystal structures of the IgG Fc fragment complexes with FcγRI. It was concluded that the folding back of FcγRI into a "seahorse" conformation ensures 1:1 binding and high-affinity interaction, giving an effective and regulated immune response to remove foreign antigens. This thesis furthers our understanding of the conformations of human IgG and their association with disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available