Structure of a fucosylated and an afucosylated IgG1 Fc bound to FcγRIIIA-158V, as determined by Ferrara et al.85 Top panel, “front” view. The 2 CH2 domains asymetrically bind to the extracellular domain 1 (EC1) of FcγRIIIA. The polymorphic residue FcγRIIIA-158 (represented as spheres) is in close contact with residues of the IgG1 Fc B chain and directly influences Fc-FcγRIIIA interaction. The CH2 N-glycans, anchored at Asn297 (Eu numbering), are face to face in the center of the Fc, and their nonreducing ends point in the direction of the CH3 domains. In the fucosylated Fc (A), the N-glycans (fx1) are composed of 4 GlcNAc residues (blue), 3 Man residues (green), and 1 fucose residue (red), attached to Asn. In the afucosylated Fc (B), the N-glycans (fx2) lack fucose and contain an additional bisecting GlcNAc residue, highlighted in violet. Two FcγRIIIA N-glycans are present: the first one is anchored at Asn45 in the EC2 domain (only its 2 first GlcNAc residues are visible but its antennae should point in the direction of the CH2 domain of the Fc B chain), and the second one at Asn162 (represented with its 2 GlcNAc and its 3 Man residues; fx3) is in great part masked by the N-glycan of the Fc A chain. Whether the Fc is fucosylated (A) or not (B), the overall structure is about the same. Middle panel, “side” view, after a 90° rotation of the top panel. The N-glycan of the Fc B chain has been masked for clarity. The FcγRIIIA Asn162 N-glycan is more visible (paler colors according to the Fc Asn297 N-glycan); its nonreducing ends (high mannose in case of NK cells) diverge from the Fc. These 2 glycans nevertheless directly interact through their core residues (GlcNAc and Fuc in panel C, GlcNAc only in panel D). Bottom panel, Enlargement of the middle panel. The presence of the bisecting GlcNAc residue (violet) in the afucosylated Fc (F) does not modify the orientation of the Fc N-glycan, but the presence of a fucose (E) pushes away the FcγRIIIA Asn162 N-glycan, creating a steric hindrance and reducing Fc-FcγRIIIA affinity. The figures were generated from structures available in the Protein Data Bank, under accession numbers 3SGF for the fucosylated Fc bound to FcγRIIIA-158V and 3SGK for the afucosylated Fc bound to FcγRIIIA-158V, using the PyMOL Molecular Graphics System, version 1.7.4.
