Identification of Residues in the First Domain of Human Fcα Receptor Essential for Interaction with IgA

Abstract

The FcR family contains multiple receptors for Igs, of which the most distantly related (∼20%) is the IgA receptor (human FcαR), being more homologous (∼35%) to another family of killer-inhibitory receptor-related immunoreceptors with a 19q13.4 chromosomal location in humans. This study of the FcαR demonstrated that, like several IgG receptors, FcαR is a low affinity receptor for Ab (Ka ∼ 106 M−1). Rapid dissociation of the rsFcαR:IgA complex (t1/2 ∼ 25 s) suggests that monomer IgA would bind transiently to cellular FcαRs, while IgA immune complexes could bind avidly. Mutagenesis of histidyl 85 and arginyl 82, in the FG loop of domain 1, demonstrated that these residues were essential for the IgA-binding activity of FcαR, while arginyl 87 makes a minor contribution to the binding activity of the receptor. This site is unusual among the Fc receptors (FcγRII, FcγRIII, and FcεRI), in which the ligand binding site is in domain 2 rather than domain 1, but like FcαR, the FG loop comprises part of the ligand binding site. The putative F and G strands flanking the FcαR ligand binding site are highly homologous in the other killer-inhibitory receptor-related immunoreceptors, suggesting they comprise a conserved structural element on which divergent FG loops are presented and participate in the specific ligand interactions of each of these receptors.