Wurzburg, Beth A; Kim, Beomkyu; Tarchevskaya, Svetlana S; Eggel, Alexander; Vogel, Monique; Jardetzky, Theodore S (2012). An engineered disulfide bond reversibly traps the IgE-Fc3-4 in a closed, nonreceptor binding conformation. Journal of biological chemistry, 287(43), pp. 36251-7. Bethesda, Md.: American Society for Biochemistry and Molecular Biology 10.1074/jbc.M112.407502
Full text not available from this repository. (Request a copy)IgE antibodies interact with the high affinity IgE Fc receptor, FcεRI, and activate inflammatory pathways associated with the allergic response. The IgE-Fc region, comprising the C-terminal domains of the IgE heavy chain, binds FcεRI 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, FcεRIα. 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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute for Immunology [discontinued] |
UniBE Contributor: |
Eggel, Alexander, Vogel, Monique |
ISSN: |
0021-9258 |
Publisher: |
American Society for Biochemistry and Molecular Biology |
Language: |
English |
Submitter: |
Factscience Import |
Date Deposited: |
04 Oct 2013 14:37 |
Last Modified: |
05 Dec 2022 14:11 |
Publisher DOI: |
10.1074/jbc.M112.407502 |
PubMed ID: |
22948141 |
Web of Science ID: |
000310364000046 |
URI: |
https://boris.unibe.ch/id/eprint/15094 (FactScience: 222287) |
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