The structure of human CD23 and its interactions with IgE and CD21

Abstract

The low-affinity immunoglobulin E (IgE) receptor, CD23 (FcɛRII), binds both IgE and CD21 and, through these interactions, regulates the synthesis of IgE, the antibody isotype that mediates the allergic response. We have determined the three-dimensional structure of the C-type lectin domain of CD23 in solution by nuclear magnetic resonance spectroscopy. An analysis of concentration-dependent chemical shift perturbations have allowed us to identify the residues engaged in self-association to the trimeric state, whereas ligand-induced changes have defined the binding sites for IgE and CD21. The results further reveal that CD23 can bind both ligands simultaneously. Despite the C-type lectin domain structure, none of the interactions require calcium. We also find that IgE and CD23 can interact to form high molecular mass multimeric complexes. The interactions that we have described provide a solution to the paradox that CD23 is involved in both up- and down-regulation of IgE and provide a structural basis for the development of inhibitors of allergic disease.

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

“…4A may reflect the slightly lower affinity reported for sFcεRIα binding to Fcε3-4 compared with IgE-Fc (5, 21, 38)]. derCD23 can similarly cause almost complete displacement of sFcεRIα, although much higher concentrations are required, greater than 100 μM, to overcome its lower affinity (K D ∼ 10 −5 -10 −6 M) (4)(5)(6)(7)(8).…”

“…At the cell surface, mCD23 is trimeric (9,31,32), and sCD23 fragments shed from the membrane that contain sufficient stalk region are also trimeric (31), although the structure of the trimer has only been modeled either on the basis of the structures of other C-type lectins (25) or guided by NMR chemical shift data (6). In the crystal structure of the complex reported here, two derCD23 "heads" bind to IgE, one to each heavy chain at a location between the Cε3 and Cε4 domains, and remote from the FcεRI binding site.…”

“…In contrast, CD23 (FcεRII), expressed on B cells, consists of three C-type lectin "head" domains connected to the membrane by a trimeric α-helical coiled-coil "stalk" (3). A single head domain binds to IgE-Fc with lower affinity (K A = 10 5 -10 6 M −1 ) than FcεRI (4)(5)(6)(7)(8), although avidity of the trimer can substantially enhance this interaction (7,(9)(10)(11). Membrane CD23 (mCD23) is cleaved from the cell surface by endogenous proteases such as ADAM10 (12,13) to yield soluble trimeric and monomeric forms (sCD23), which have been implicated in both positive and negative feedback mechanisms for the regulation of IgE synthesis by B cells that have switched to IgE production (1,7,8,(14)(15)(16).…”

“…Both receptors bind to the Cε3 domains of IgE-Fc (1,6,(19)(20)(21). Cε2 was also implicated in FcεRI binding (5), but crystal structures of the sFcεRIα-Fcε3-4 complex (20) (Fcε3-4 is a subfragment of IgE-Fc consisting of a dimer of the Cε3 and Cε4 domains) and most recently the sFcεRIα-IgE-Fc complex, including the Cε2 domains, show that the Cε2 domains exert their influence only indirectly upon the formation of this 1:1 complex (21).…”

Expression of complement receptors 1 (CR1/CD35) and 2 (CR2/CD21), and co-signaling molecule CD19 in cattle

“…C3dg is the bound remnant of C3b, resulting from its cleavage and inactivation, and can be further reduced to C3d by trypsin. In humans, CR2 also binds to the low--afBinity Fc ε receptor II (CD23) (Aubry et al, 1992;Hibbert et al, 2005) and to IFN--α , and acts as the obligate receptor for the Epstein Barr virus (EBV) (Fingeroth et al, 1984). In both mice and humans, CR2 is expressed on B lymphocytes (Fingeroth et al, 1989;Jacobson & Weis, 2008;Weis et al, 1984) and follicular dendritic cells (Reynes et al, 1985;Liu et al, 1997;Ling et al, 1998); CR2 is also expressed on human epithelial cells (Birkenbach et al, 1992).…”