The interaction of Fc alpha RI with IgA and its implications for ligand binding by immunoreceptors of the leukocyte receptor cluster

This study defines the molecular basis of the Fc alpha RI (CD89):IgA intera ction, which is distinct from that of the other leukocyte Fc receptors and their Ig ligands, A comprehensive analysis using both cell-free (biosensor) and cell-based assays was used to define and characterize the IgA binding region of Fc alpha RI. Biosensor analysis of mutant Fc alpha RI proteins sh owed that residues Y35, Y81, and R82 were essential for IgA binding, and R5 2 also contributed. The role of the essential residues (Y35 and R82) was co nfirmed by analysis of mutant receptors expressed on the surface of mammali an cells. These receptors failed to bind IgA, but were detected by the mAb MY43, which blocks IgA binding to Fc alpha RI, indicating that its epitope does not coincide with these IgA binding residues. A homology model of the ectodomains of Fc alpha RI was generated based on the structures of killer Ig-like receptors, which share 30-34% identity with Fc alpha RI, Key struct ural features of killer Ig-like receptors are appropriately reproduced in t he model, including the structural conservation of the interdomain linker a nd hydrophobic core (residues V17, V97, and W183), In this Fc alpha RI mode l the residues forming the IgA binding site identified by mutagenesis form a single face near the N-terminus of the receptor, distinct from other leuk ocyte Fc receptors where ligand binding is in the second domain. This taken together with major differences in kinetics and affinity for IgA:Fc alpha RI interaction that were observed depending on whether Fc alpha RI was immo bilized or in solution suggest a mode of interaction unique among the leuko cyte receptors.