IgGReceptor Interactions

FcyR

Several crystal structures are now available for the extracellular domains of FcyRII [7-9] and FcyRIII [10,11], which show (together with FceRI [12,13]) that they are all remarkably similar, as expected from their highly homologous sequences. There is an acute angle between the two Ig-like domains, which pack against each other around a hydrophobic interface. In the structure of the complex between FcyRIII and IgG Fc, first determined by Sondermann et al. in 2000 [10], loops from the a2 domain and part of the linker region between the two domains of the receptor protrude into the space between the two Cy2 domains of the Fc just below the hinge region. Thus, there are two distinct regions of interaction, one on each of the heavy chains, which involve residues of the lower hinge and Cy2 domains (Fig. 2A). Upon binding, the IgG Fc opens up slightly and the Cy2 domains move apart compared with uncomplexed IgG Fc; at the same time, the angle between the two receptor domains increases (from 70 to 80°), compared with the free receptor structures [10]. The uncomplexed IgG Fc was initially twofold symmetric and thus in principle might have been expected to bind to two receptors, but the distortion of this symmetry upon binding to the receptor, and the fact that the receptor lies on the approximate two-fold axis of the complex (Fig. 2A), ensures a stoichiometry of 1:1. This is essential if free IgG is not to cross-link receptor in the absence of antigen [14]. The orientation of the IgG Fc bound to the receptor clearly implies that the Fab arms of the IgG molecule must be bent at the hinge; the overall topology is depicted in Fig. 2A.

The structure of the FcyRIII/IgG Fc complex has subsequently been determined by others in a different crystal form [15], and the structure is virtually identical. In neither structure do the two N-linked oligosaccharide chains (at Asn297 in each Cy2 domain) contribute directly to receptor binding, but they probably serve to stabilize the Fc domains in the binding region, as removal of carbohydrate from IgG Fc severely reduces its receptor binding capacity [16,17].

Because the extracellular Fc-binding domains of the FcyRI and FcyRII are so similar, (as are the Fc regions of the different subclasses of human IgG), the FcyR/IgG Fc complexes are all likely to be essentially similar in structure [9]. There are however, differences in affinity and binding kinetics between the different FcyR and the various human subclasses of IgG [1,2,18], and these presumably result from minor differences in the nature of the residues at the interface [9]. More intriguing is the striking difference between the affinity and kinetics of binding of IgE to FceRI compared with IgG to its receptors; we shall return to this issue later.

FcRn

The neonatal Fc receptor closely resembles a class I MHC molecule, complete with a p2-microglobulin chain (P2-m), but the peptide-binding groove formed between the a1 and a2 domains is too narrow and is nonfunctional [5]. In the complex with IgG Fc, recently determined at higher resolution [19] following an earlier low-resolution study [20], FcRn interacts through residues of the a2 domain, with some contacts from p2-m. The region on Fc to which it binds is the cleft between the Cy2 and Cy3, distant from the FcyR binding site (Fig. 2B). IgG binds to FcRn with nanomolar affinity at acidic pH (in transport vesicles), but releases it at neutral pH (in the blood). The binding interface accounts for these properties, as it is both very extensive (1870 A2) and includes four salt bridges, three of which involve histidine residues on Fc and either aspartic or glutamic residues on FcRn. At pH < 6.5, the histidines are protonated and form salt bridges, whereas at pH > 7.0 they are neutral and the salt bridges are lost. The crystal structure also appears to show that quaternary structural differences resulting from binding to one Fc heavy chain alter the binding site on the other chain, thus accounting for the observed negative cooperativity in binding a second IgG molecule to the receptor. A common feature of IgG binding to both FcyR and FcRn, therefore, is a distortion of the two-fold symmetry inherent in the Fc region of the free antibody molecule, resulting in either a partial (FcRn) or total loss of Fc binding at the second site. Another similarity is the orientation of the Fc relative to the membrane (Fig. 2B), again implying a bend between the Fc and the Fab arms of the antibody.

Neonatal Receptor

Figure 2 (A) IgG Fc/sFcyRIII complex (PDB code 1E4K) and schematic (rotated view) to show the disposition of the IgG molecule and its Fab arms relative to the membrane. (B) IgG Fc/FcRn complex (PDB code 1I1A) and schematic (same orientation) to show the disposition of the Fc relative to the membrane, again implying that the IgG must be bent. (C) IgE Fc£3-4/sFc£RIa complex (PDB code 1F6A) and schematic (rotated view) to show the complete Fc (with Ce2 domains), the Fab arms, and the conformational change that is proposed to lead to high-affinity binding.

event complex

Figure 2 (A) IgG Fc/sFcyRIII complex (PDB code 1E4K) and schematic (rotated view) to show the disposition of the IgG molecule and its Fab arms relative to the membrane. (B) IgG Fc/FcRn complex (PDB code 1I1A) and schematic (same orientation) to show the disposition of the Fc relative to the membrane, again implying that the IgG must be bent. (C) IgE Fc£3-4/sFc£RIa complex (PDB code 1F6A) and schematic (rotated view) to show the complete Fc (with Ce2 domains), the Fab arms, and the conformational change that is proposed to lead to high-affinity binding.

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