Fc?RI binding at the IgA1 CH2-CH3 interface induces long-range conformational changes that are transmitted to the hinge region.

ABSTRACT: IgA effector functions include proinflammatory immune responses triggered upon clustering of the IgA-specific receptor, Fc?RI, by IgA immune complexes. Fc?RI binds to the IgA1-Fc domain (Fc?) at the CH2-CH3 junction and, except for CH2 L257 and L258, all side-chain contacts are contributed by the CH3 domain. In this study, we used experimental and computational approaches to elucidate energetic and conformational aspects of Fc?RI binding to IgA. The energetic contribution of each IgA residue in the binding interface was assessed by alanine-scanning mutagenesis and equilibrium surface plasmon resonance (SPR). As expected, hydrophobic residues central to the binding site have strong energetic contributions to the Fc?RI:Fc? interaction. Surprisingly, individual mutation of CH2 residues L257 and L258, found at the periphery of the Fc?RI binding site, dramatically reduced binding affinity. Comparison of antibody:receptor complexes involving IgA or its precursor IgY revealed a conserved receptor binding site at the CH2-CH3 junction (or its equivalent). Given the importance of residues near the CH2-CH3 junction, we used coarse-grained Langevin dynamics simulations to understand the functional dynamics in Fc?. Our simulations indicate that Fc?RI binding, either in an asymmetric (1:1) or symmetric (2:1) complex with Fc?, propagated long-range conformational changes across the Fc domains, potentially impacting the hinge and Fab regions. Subsequent SPR experiments confirmed that Fc?RI binding to the Fc? CH2-CH3 junction altered the kinetics of HAA lectin binding at the IgA1 hinge. Receptor-induced long-distance conformational transitions have important implications for the interaction of aberrantly glycosylated IgA1 with anti-glycan autoantibodies in IgA nephropathy.

SUBMITTER: Posgai MT 

PROVIDER: S-EPMC6156678 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature