FcγRIIB I232T polymorphic change allosterically suppresses ligand binding

Abstract

Fc{gamma}RIIB bindings to its ligand suppress immune cell activation. A single-nucleotide polymorphic (SNP) change, I232T, in the transmembrane (TM) domain of Fc{gamma}RIIB loses its suppression function, which clinically associates with systemic lupus erythematosus (SLE). Previously, we reported that I232T tilts Fc{gamma}RIIBs TM domain. In this study, combining with molecular dynamics simulations and single-cell FRET assay, we further revealed that such tilting by I232T unexpectedly bends the Fc{gamma}RIIBs ectodomain towards plasma membrane to allosterically impede Fc{gamma}RIIBs ligand association. We then used single-cell biomechanical assay to further find out that I232T also reduces two-dimensional in-situ binding affinities and association rates of Fc{gamma}RIIB interacting with its ligands by three-folds. This allosteric regulation by a SNP provides an intrinsic molecular mechanism for functional loss of Fc{gamma}RIIB-I232T in SLE patients.