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Characterization of interactions within the Igα/Igβ transmembrane domains of the human B-cell receptor provides insights into receptor assembly
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Lockey, Christine, Young, Hannah, Brown, Jessica and Dixon, Ann M. (2022) Characterization of interactions within the Igα/Igβ transmembrane domains of the human B-cell receptor provides insights into receptor assembly. Journal of Biological Chemistry, 298 (5). 101843. doi:10.1016/j.jbc.2022.101843 ISSN 0021-9258.
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Official URL: https://doi.org/10.1016/j.jbc.2022.101843
Abstract
The B-cell receptor (BCR), a complex comprised of a membrane-associated immunoglobulin (mIg) and the Ig/ heterodimer, is one of the most important immune receptors in humans and controls B-cell development, activity, selection, and death. BCR signaling plays key roles in autoimmune diseases and lymphoproliferative disorders yet, despite the clinical significance of this protein complex, key regions (i.e. the transmembrane domains) have yet to be structurally characterized. The mechanism for BCR signaling also remains unclear, and has been variously described by the mutually exclusive crosslinking and dissociation activation models. Common to these models is the significance of local plasma membrane composition, which implies that interactions between BCR transmembrane domains (TMDs) play a role in receptor functionality. Here we used an in vivo assay of TMD oligomerization called GALLEX alongside spectroscopic and computational methods to characterize the structures and interactions of human Ig and Ig TMDs in detergent micelles and natural membranes. We observed weak self-association of the Igb TMD and strong self-association of the Iga TMD, which scanning mutagenesis revealed was entirely stabilized by an E-X10-P motif. We also demonstrated strong heterotypic interactions between the Iga and Igb TMDs both in vitro and in vivo, which scanning mutagenesis and computational models suggest is multiconfigurational but can accommodate distinct interaction sites for self- and heterotypic interactions of the Iga TMD. Taken together, these results demonstrate that the TMDs of the human B-cell receptor are sites of strong protein-protein interactions that may direct BCR assembly, ER retention, and immune signaling.
| Item Type: | Journal Article | ||||||||
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| Subjects: | Q Science > QD Chemistry Q Science > QP Physiology Q Science > QR Microbiology |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||
| Library of Congress Subject Headings (LCSH): | B cells -- Receptors, Circular dichroism , Membrane proteins -- Metabolism, Protein-protein interactions , Lipids , Proteins -- Crosslinking | ||||||||
| Journal or Publication Title: | Journal of Biological Chemistry | ||||||||
| Publisher: | American Society for Biochemistry and Molecular Biology | ||||||||
| ISSN: | 0021-9258 | ||||||||
| Official Date: | May 2022 | ||||||||
| Dates: |
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| Volume: | 298 | ||||||||
| Number: | 5 | ||||||||
| Article Number: | 101843 | ||||||||
| DOI: | 10.1016/j.jbc.2022.101843 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||||||
| Copyright Holders: | © 2022 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. | ||||||||
| Date of first compliant deposit: | 7 April 2022 | ||||||||
| Date of first compliant Open Access: | 8 April 2022 | ||||||||
| RIOXX Funder/Project Grant: |
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