4gt7

Publication Abstract from PubMed

IgE antibodies interact with the high affinity IgE Fc receptor, FcepsilonRI, and activate inflammatory pathways associated with the allergic response. The IgE-Fc region, comprising the C-terminal domains of the IgE heavy chain, binds FcepsilonRI and can adopt different conformations ranging from a closed form incompatible with receptor binding to an open, receptor-bound state. A number of intermediate states are also observed in different IgE-Fc crystal forms. To further explore this apparent IgE-Fc conformational flexibility and to potentially trap a closed, inactive state, we generated a series of disulfide bond mutants. Here we describe the structure and biochemical properties of an IgE-Fc mutant that is trapped in the closed, non-receptor binding state via an engineered disulfide at residue 335 (Cys-335). Reduction of the disulfide at Cys-335 restores the ability of IgE-Fc to bind to its high affinity receptor, FcepsilonRIalpha. The structure of the Cys-335 mutant shows that its conformation is within the range of previously observed, closed form IgE-Fc structures and that it retains the hydrophobic pocket found in the hinge region of the closed conformation. Locking the IgE-Fc into the closed state with the Cys-335 mutation does not affect binding of two other IgE-Fc ligands, omalizumab and DARPin E2_79, demonstrating selective blocking of the high affinity receptor binding.

An engineered disulfide bond reversibly traps the IgE-Fc3-4 in a closed, nonreceptor binding conformation.,Wurzburg BA, Kim B, Tarchevskaya SS, Eggel A, Vogel M, Jardetzky TS J Biol Chem. 2012 Oct 19;287(43):36251-7. doi: 10.1074/jbc.M112.407502. Epub 2012, Sep 4. PMID:22948141^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.