FcγRIIB I232T polymorphic change allosterically suppresses ligand binding [article]

Wei Hu, Yong Zhang, Xiaolin Sun, Liling Xu, Hengyi Xie, Zhanguo Li, Wanli Liu, Jizhong Lou, Wei Chen
2019 bioRxiv   pre-print
AbstractFcγRIIB bindings to its ligand suppress immune cell activation. A single-nucleotide polymorphic (SNP) change, I232T, in the transmembrane (TM) domain of FcγRIIB loses its suppression function, which clinically associates with systemic lupus erythematosus (SLE). Previously, we reported that I232T tilts FcγRIIB's 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
more » ... ectodomain towards plasma membrane to allosterically impede FcγRIIB's 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 FcγRIIB interacting with its ligands by three-folds. This allosteric regulation by a SNP provides an intrinsic molecular mechanism for functional loss of FcγRIIB-I232T in SLE patients.
doi:10.1101/586487 fatcat:5tywhc4pfzekfbrski7ck7id3i