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Title: Molecular determinants for Fc-gamma-receptor mediated phagocytosis and transmembrane interactions between receptor subunits
Author: Hutchinson, M. J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1997
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FcγRI associates with the homodimeric γ-chain of the high affinity receptor for IgE (FcγRI). This receptor subunit has a cytoplasmic consensus sequence identified in several immunoreceptor signalling polypeptides known as the Immunoreceptor Tyrosine Activation Motif (ITAM). Here a functional role of this association is demonstrated. Whilst COS-7 cells transfected with FcγRI alone were unable to mediate phagocytosis, cells co-transfected with FcγRI and γ-chain could mediate phagocytosis in a tyrosine kinase dependent manner. Tail truncation mutants of FcγRI demonstrate that this interaction between FcγRI and γ-chain is within the transmembrane domain. Recognition of multiple IgG molecules on the opsonised target by FcγRI results in clustering of this receptor. This serves to aggregate the ITAMs of the associated γ-chain through non-covalent interactions between the two molecules thus initiating the phagocytic signal transduction cascade. Using a panel of chimeric receptors, the importance of the cytoplasmic ITAM was confirmed and the ligand independence of phagocytosis demonstrated. Replacing the γ-chain cysteine with an alanine had no effect on the ability of this subunit to transduce the phagocytic signal or to enhance the binding affinity of FcγRI for IgG. However, the strength of the physical association between γ-chain and FcγRI appears to be diminished, (as assessed by co-immunoprecipitation data). In addition to defining the molecular determinants for Fc receptor mediated phagocytosis, these results suggest a valuable model system for investigating protein-protein interactions within the plasma-membrane.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available