Crystal structure of IgE bound to its B-cell receptor CD23 reveals a mechanism of reciprocal allosteric inhibition with high affinity receptor FcεRI

Abstract

The role of IgE in allergic disease mechanisms is performed principally through its interactions with two receptors, FcεRI on mast cells and basophils, and CD23 (FcεRII) on B cells. The former mediates allergic hypersensitivity, the latter regulates IgE levels, and both receptors, also expressed on antigen-presenting cells, contribute to allergen uptake and presentation to the immune system. We have solved the crystal structure of the soluble lectin-like "head" domain of CD23 (derCD23) bound to a subfragment of IgE-Fc consisting of the dimer of Cε3 and Cε4 domains (Fcε3-4). One CD23 head binds to each heavy chain at the interface between the two domains, explaining the known 2:1 stoichiometry and suggesting mechanisms for crosslinking membrane-bound trimeric CD23 by IgE, or membrane IgE by soluble trimeric forms of CD23, both of which may contribute to the regulation of IgE synthesis by B cells. The two symmetrically located binding sites are distant from the single FcεRI binding site, which lies at the opposite ends of the Cε3 domains. Structural comparisons with both free IgE-Fc and its FcεRI complex reveal not only that the conformational changes in IgE-Fc required for CD23 binding are incompatible with FcεRI binding, but also that the converse is true. The two binding sites are allosterically linked. We demonstrate experimentally the reciprocal inhibition of CD23 and FcεRI binding in solution and suggest that the mutual exclusion of receptor binding allows IgE to function independently through its two receptors.antibody-receptor interactions | X-ray crystallography

Diversification of IgG effector functions

“…In contrast, Type II FcγRs are C-type lectin receptors, which exhibit diverse ligand specificity (3). Indeed, in addition to interacting with the Fc domain of IgG, Type II FcγRs have the capacity to engage diverse ligands, including carbohydrate structures, heavily glycosylated proteins and IgE (4)(5)(6).…”

General mechanism for modulating immunoglobulin effector function

“…The intrinsic flexibility of the IgE Ce3 domain results in both open and closed conformations of the IgE Fc, resulting in the binding of either FceRI or CD23, respectively. Binding of either receptor induces an allosteric change in the IgE Fc to the alternative conformation, thus precluding the interaction with the other receptor (7). Binding of IgE to the type II, C-type lectin CD23 is neither carbohydrate-nor calcium-dependent, mediated exclusively through protein-protein interactions, generating a 2:1 complex of CD23 with the Ce3-Ce4 interface (7).…”

“…By contrast, both IgG and IgE can engage a second class of receptors, the evolutionarily related, C-type lectins dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) (3) and CD23 (4), respectively, resulting in anti-inflammatory and immunosuppressive responses (5,6). The structural basis for the ability of IgE to interact either with one or the other of these two disparate classes of receptors has recently been defined (7). The intrinsic flexibility of the IgE Ce3 domain results in both open and closed conformations of the IgE Fc, resulting in the binding of either FceRI or CD23, respectively.…”

“…Binding of either receptor induces an allosteric change in the IgE Fc to the alternative conformation, thus precluding the interaction with the other receptor (7). Binding of IgE to the type II, C-type lectin CD23 is neither carbohydrate-nor calcium-dependent, mediated exclusively through protein-protein interactions, generating a 2:1 complex of CD23 with the Ce3-Ce4 interface (7). DC-SIGN is a structurally homologous, calcium-dependent, carbohydratebinding, type II lectin, tightly linked to CD23 on chromosome 19 (8), displaying ligand specificity for mannose-containing glycoconjugates and fucose-containing Lewis antigens.…”

An Engineered Disulfide Bond Reversibly Traps the IgE-Fc3–4 in a Closed, Nonreceptor Binding Conformation

“…Similarly, the structure of the IgE-Fc 2-4 protein in the absence of receptor shows a partially closed state that would require opening of the C⑀3 domains to bind receptor (16,17). Recently, the structure of the IgE-Fc 3-4 in complex with the low affinity IgE receptor (CD23) has been determined, demonstrating that CD23 binds to the C⑀3-4 hinge region, favoring a closed conformation for the Fc (18).…”