Mechanism and functional implications of the heme-induced binding promiscuity of IgE

Biochemistry
Maya HadzhievaJordan D Dimitrov

Abstract

A fraction of antibodies from healthy immune repertoires binds to heme and acquires the ability to recognize multiple antigens. The mechanism and functional consequences of heme-mediated antigen binding promiscuity (polyreactivity) are not understood. Here, we used SPE7, a mouse monoclonal IgE specific for dinitrophenyl that has been thoroughly characterized at the molecular level, as a model antibody to elucidate the mechanism and functional consequences of heme-mediated polyreactivity. We first demonstrate that exposure of SPE7 to heme results in a substantial increase in its antigen binding polyreactivity. Comparison of the binding kinetics and thermodynamics of interaction of native and heme-bound SPE7 indicates that the binding of heme to SPE7 confers binding affinities in the low nanomolar range toward several antigens but has no influence on the mechanism of recognition of dinitrophenyl. In vitro cellular assays further demonstrate that heme-bound SPE7 does not promote the degranulation of basophils in the presence of new target antigens, while degranulation is observed in the presence of dinitrophenyl. Molecular docking and fluorescence spectroscopy revealed binding of heme to the variable region of SPE7 at a distance f...Continue Reading

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Citations

Mar 2, 2016·Biochemical and Biophysical Research Communications·Maya HadzhievaJordan D Dimitrov
Feb 6, 2019·Nature Reviews. Immunology·Alexia KanyavuzJordan D Dimitrov
Dec 21, 2019·ACS Omega·Nina BožinovićJordan D Dimitrov

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