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Published on: November 1, 2014
Domain one of the high affinity IgE receptor, FcepsilonRI, regulates binding to IgE through its interface with domain
L J Rigby1, V C Epa, G A Mackay
1Helen M. Schutt Laboratory for Immunology, Austin Research Institute, Kronheimer Building, Austin Repatriation Medical Centre, Heidelberg, Victoria, 3084, Australia.
Insights
The first domain of the high-affinity IgE receptor (FcepsilonRI) structurally supports IgE binding, despite the second domain mediating direct contact. Specific mutations reveal its crucial role in maintaining the ligand-binding site integrity.
Area of Science:
- Immunology
- Structural Biology
- Protein Interactions
Background:
- The high-affinity receptor for IgE (FcepsilonRI) binds immunoglobulin E (IgE).
- The second Ig-like domain of the alpha subunit mediates direct IgE binding.
- The functional role of the first Ig-like domain of FcepsilonRI remains incompletely understood.
Purpose of the Study:
- To elucidate the structural and functional role of the first Ig-like domain of FcepsilonRI in IgE binding.
- To investigate the contribution of specific residues in the first domain to receptor-ligand interactions.
Main Methods:
- Analysis of chimeric receptors and point mutants of FcepsilonRI.
- Homology modeling of FcepsilonRI-alpha based on FcgammaRIIa structure.
- Assessment of IgE binding affinity following mutations.
Main Results:
- The first domain of FcepsilonRI plays a critical structural role in presenting the IgE-binding site.
- Specific residues (Arg15, Phe17) in the A' strand of the first domain are essential for maintaining the interdomain interface and IgE binding.
- Mutations leading to interface collapse result in loss of ligand binding.
- Discrepancies in previous studies can be explained by the presence or absence of Arg15.
Conclusions:
- The second domain of FcepsilonRI-alpha directly contacts IgE.
- The first domain is crucial for maintaining the structural integrity of the interdomain interface and, consequently, the IgE-binding site.
- Understanding FcepsilonRI structure provides insights into allergic responses and therapeutic strategies.
Abstract:
The high affinity receptor for IgE, FcepsilonRI, binds IgE through the second Ig-like domain of the alpha subunit. The role of the first Ig-like domain is not well understood, but it is required for optimal binding of IgE to FcepsilonRI, either through a minor contact interaction or in a supporting structural capacity. The results reported here demonstrate that domain one of FcepsilonRI plays a major structural role supporting the presentation of the ligand-binding site, by interactions generated within the interdomain interface. Analysis of a series of chimeric receptors and point mutants indicated that specific residues within the A' strand of domain one are crucial to the maintenance of the interdomain interface, and IgE binding. Mutation of the Arg(15) and Phe(17) residues caused loss in ligand binding, and utilizing a homology model of FcepsilonRI-alpha based on the solved structure of FcgammaRIIa, it appears likely that this decrease is brought about by collapse of the interface and consequently the IgE-binding site. In addition discrepancies in results of previous studies using chimeric IgE receptors comprising FcepsilonRIalpha with either FcgammaRIIa or FcgammaRIIIA can be explained by the presence or absence of Arg(15) and its influence on the IgE-binding site. The data presented here suggest that the second domain of FcepsilonRI-alpha is the only domain involved in direct contact with the IgE ligand and that domain one has a structural function of great importance in maintaining the integrity of the interdomain interface and, through it, the ligand-binding site.
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