FcγRIIB-I232T polymorphic change allosterically suppresses ligand binding.

Area of Science:

• Immunology
• Molecular Biology
• Structural Biology

Background:

• Fc receptor gamma IIB (FcγRIIB) is crucial for regulating immune cell activation through ligand binding.
• A specific single-nucleotide polymorphism (SNP), I232T, in FcγRIIB's transmembrane domain is linked to loss of function and systemic lupus erythematosus (SLE).
• Previous research indicated that the I232T variant causes tilting of the FcγRIIB transmembrane domain.

Purpose of the Study:

• To elucidate the molecular mechanism by which the I232T SNP in FcγRIIB leads to functional loss.
• To investigate the structural and dynamic changes induced by the I232T substitution.
• To quantify the impact of I232T on FcγRIIB's interaction with its ligands.

Main Methods:

• Molecular dynamics (MD) simulations to model protein behavior.
• Single-cell Förster Resonance Energy Transfer (FRET) assay to measure molecular interactions.
• Biophysical analysis of FcγRIIB binding affinities and association rates.

Main Results:

• The I232T substitution induces a conformational change, bending the FcγRIIB ectodomain towards the plasma membrane.
• This structural alteration allosterically hinders FcγRIIB's ability to associate with its ligands.
• In situ binding affinities and association rates for IgG1, IgG2, and IgG3 ligands were reduced by 3-4 fold.

Conclusions:

• The I232T SNP causes a loss of FcγRIIB suppressive function through an allosteric mechanism.
• This SNP-induced allosteric regulation provides a direct molecular explanation for FcγRIIB dysfunction in SLE patients.
• Understanding this mechanism may inform therapeutic strategies for SLE targeting FcγRIIB signaling.