FcγRIIB-I232T polymorphic change allosterically suppresses ligand binding

eLife

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[1] Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Department of Rheumatology and Immunology, Peking-Tsinghua Center for Life Sciences, Peking University People's Hospital, Beijing, China;Department of Neurobiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China;Department of Neurobiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China;Key Laboratory for Biomedical Engineering of Ministry of Education, State Key Laboratory for Modern Optical Instrumentation, College of Biomedical Engineering and Instrument Science, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China;Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China;Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China;University of Chinese Academy of Sciences, Beijing, China;MOE Key Laboratory of Protein Sciences, Center for Life Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Institute for Immunology, Tsinghua University, Beijing, China;

关键词: FcγRIIB;    single-nucleotide polymorphism;    systemic lupus erythematosus;    in-situ 2D binding kinetics;    allosterically conformational change;    membrane receptor;    Human;   

DOI  :  10.7554/eLife.46689

来源: publisher

【 摘 要 】

10.7554/eLife.46689.001FcγRIIB binding to its ligand suppresses immune cell activation. A single-nucleotide polymorphic (SNP) change, I232T, in the transmembrane (TM) domain of FcγRIIB loses its suppressive function, which is clinically associated 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 reveal that such tilting by I232T unexpectedly bends the FcγRIIB’s ectodomain toward plasma membrane to allosterically impede FcγRIIB’s ligand association. I232T substitution reduces in situ two-dimensional binding affinities and association rates of FcγRIIB to interact with its ligands, IgG1, IgG2 and IgG3 by three to four folds. This allosteric regulation by an SNP provides an intrinsic molecular mechanism for the functional loss of FcγRIIB-I232T in SLE patients.

【 授权许可】

CC BY