دورية أكاديمية
A fluorescent biosensor reveals conformational changes in human immunoglobulin E Fc: implications for mechanisms of receptor binding, inhibition, and allergen recognition.
| العنوان: | A fluorescent biosensor reveals conformational changes in human immunoglobulin E Fc: implications for mechanisms of receptor binding, inhibition, and allergen recognition. |
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| المؤلفون: | Hunt J; MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, Guy's Hospital Campus, London SE1 1UL; The Randall Division of Cell and Molecular Biophysics, Guy's Hospital Campus, London SE1 1UL; The Division of Asthma Allergy and Lung Biology, King's College London, Guy's Hospital Campus, London SE1 1UL., Keeble AH; MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, Guy's Hospital Campus, London SE1 1UL; The Randall Division of Cell and Molecular Biophysics, Guy's Hospital Campus, London SE1 1UL; The Division of Asthma Allergy and Lung Biology, King's College London, Guy's Hospital Campus, London SE1 1UL., Dale RE; The Randall Division of Cell and Molecular Biophysics, Guy's Hospital Campus, London SE1 1UL., Corbett MK; The Randall Division of Cell and Molecular Biophysics, Guy's Hospital Campus, London SE1 1UL., Beavil RL; MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, Guy's Hospital Campus, London SE1 1UL; The Randall Division of Cell and Molecular Biophysics, Guy's Hospital Campus, London SE1 1UL; The Division of Asthma Allergy and Lung Biology, King's College London, Guy's Hospital Campus, London SE1 1UL., Levitt J; The Department of Physics, King's College London, Strand, London WC2R 2LS., Swann MJ; Farfield Group Limited, Voyager, Chicago Avenue, Manchester Airport, Manchester, M90 3DQ, United Kingdom., Suhling K; The Department of Physics, King's College London, Strand, London WC2R 2LS., Ameer-Beg S; The Randall Division of Cell and Molecular Biophysics, Guy's Hospital Campus, London SE1 1UL., Sutton BJ; MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, Guy's Hospital Campus, London SE1 1UL; The Randall Division of Cell and Molecular Biophysics, Guy's Hospital Campus, London SE1 1UL., Beavil AJ; MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, Guy's Hospital Campus, London SE1 1UL; The Randall Division of Cell and Molecular Biophysics, Guy's Hospital Campus, London SE1 1UL; The Division of Asthma Allergy and Lung Biology, King's College London, Guy's Hospital Campus, London SE1 1UL. Electronic address: andrew.beavil@kcl.ac.uk. |
| المصدر: | The Journal of biological chemistry [J Biol Chem] 2012 May 18; Vol. 287 (21), pp. 17459-17470. Date of Electronic Publication: 2012 Mar 22. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
| مواضيع طبية MeSH: | Allergens/*analysis , Biosensing Techniques/*methods , Fluorescence Resonance Energy Transfer/*methods , Green Fluorescent Proteins/*chemistry , Immunoglobulin E/*chemistry , Immunoglobulin Fc Fragments/*chemistry , Receptors, IgE/*chemistry, Antibodies, Anti-Idiotypic/chemistry ; Antibodies, Monoclonal, Humanized/chemistry ; Green Fluorescent Proteins/genetics ; HEK293 Cells ; Humans ; Immunoglobulin E/genetics ; Immunoglobulin Fab Fragments/chemistry ; Immunoglobulin Fab Fragments/genetics ; Omalizumab ; Receptors, IgE/genetics ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/genetics |
| مستخلص: | IgE binding to its high affinity receptor FcεRI on mast cells and basophils is a key step in the mechanism of allergic disease and a target for therapeutic intervention. Early indications that IgE adopts a bent structure in solution have been confirmed by recent x-ray crystallographic studies of IgEFc, which further showed that the bend, contrary to expectation, is enhanced in the crystal structure of the complex with receptor. To investigate the structure of IgEFc and its conformational changes that accompany receptor binding in solution, we created a Förster resonance energy transfer (FRET) biosensor using biologically encoded fluorescent proteins fused to the N- and C-terminal IgEFc domains (Cε2 and Cε4, respectively) together with the theoretical basis for quantitating its behavior. This revealed not only that the IgEFc exists in a bent conformation in solution but also that the bend is indeed enhanced upon FcεRI binding. No change in the degree of bending was seen upon binding to the B cell receptor for IgE, CD23 (FcεRII), but in contrast, binding of the anti-IgE therapeutic antibody omalizumab decreases the extent of the bend, implying a conformational change that opposes FcεRI engagement. HomoFRET measurements further revealed that the (Cε2)(2) and (Cε4)(2) domain pairs behave as rigid units flanking the conformational change in the Cε3 domains. Finally, modeling of the accessible conformations of the two Fab arms in FcεRI-bound IgE revealed a mutual exclusion not seen in IgG and Fab orientations relative to the membrane that may predispose receptor-bound IgE to cross-linking by allergens. |
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| معلومات مُعتمدة: | G0501494 United Kingdom MRC_ Medical Research Council; 085944 United Kingdom Wellcome Trust; 076343 United Kingdom Wellcome Trust; BB/D011086/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; G1100090-E01/1 United Kingdom MRC_ Medical Research Council; G1100090 United Kingdom MRC_ Medical Research Council; G1000758 United Kingdom MRC_ Medical Research Council; G0501494(76353) United Kingdom MRC_ Medical Research Council |
| فهرسة مساهمة: | Indexing Agency: NLM Local ID #: EMS48341. |
| المشرفين على المادة: | 0 (Allergens) 0 (Antibodies, Anti-Idiotypic) 0 (Antibodies, Monoclonal, Humanized) 0 (Immunoglobulin Fab Fragments) 0 (Immunoglobulin Fc Fragments) 0 (Receptors, IgE) 0 (Recombinant Fusion Proteins) 147336-22-9 (Green Fluorescent Proteins) 2P471X1Z11 (Omalizumab) 37341-29-0 (Immunoglobulin E) |
| تواريخ الأحداث: | Date Created: 20120324 Date Completed: 20120723 Latest Revision: 20240417 |
| رمز التحديث: | 20240417 |
| مُعرف محوري في PubMed: | PMC3366799 |
| DOI: | 10.1074/jbc.M111.331967 |
| PMID: | 22442150 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1083-351X |
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| DOI: | 10.1074/jbc.M111.331967 |