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BTN3A1 Discriminates γδ T Cell Phosphoantigens from Nonantigenic Small Molecules via a Conformational Sensor in Its B30.2 Domain

Salim, Mahboob; Knowles, Timothy J; Baker, Alfie T.; Davey, Martin S.; Jeeves, Mark; Sridhar, Pooja; Wilkie, John; Willcox, Carrie R.; Kadri, Hachemi; Taher, Taher E.; Vantourout, Pierre; Hayday, Adrian; Mehellou, Youcef; Mohammed, Fiyaz; Willcox, Benjamin E.

BTN3A1 Discriminates γδ T Cell Phosphoantigens from Nonantigenic Small Molecules via a Conformational Sensor in Its B30.2 Domain Thumbnail


Authors

Mahboob Salim

Timothy J Knowles

Alfie T. Baker

Martin S. Davey

Mark Jeeves

Pooja Sridhar

John Wilkie

Carrie R. Willcox

Hachemi Kadri

Taher E. Taher

Pierre Vantourout

Adrian Hayday

Youcef Mehellou

Fiyaz Mohammed

Benjamin E. Willcox



Abstract

Human Vγ9/Vδ2 T-cells detect tumour cells and microbial infections by recognising small phosphorylated prenyl metabolites termed phosphoantigens (P-Ag). The type-1 transmembrane protein Butyrophilin 3A1 (BTN3A1) is critical to the P-Ag-mediated activation of Vγ9/Vδ2 T-cells, however, the molecular mechanisms involved in BTN3A1-mediated metabolite sensing are unclear, including how P-Ag are discriminated from non-antigenic small molecules. Here, we utilised NMR and X-ray crystallography to probe P-Ag sensing by BTN3A1. Whereas the BTN3A1 Immunoglobulin Variable domain failed to bind P-Ag, the intracellular B30.2 domain bound a range of negativelycharged small molecules, including P-Ag, in a positively-charged surface pocket. However, NMR chemical shift perturbations indicated BTN3A1 discriminated P-Ag from non-antigenic small molecules by their ability to induce a specific conformational change in the B30.2 domain that propagated from the P-Ag binding site to distal parts of the domain. These results suggest BTN3A1 selectively detects P-Ag intracellularly via a conformational antigenic sensor in its B30.2 domain, and have implications for rational design of antigens for Vγ9/Vδ2 -based T-cell immunotherapies.

Citation

Salim, M., Knowles, T. J., Baker, A. T., Davey, M. S., Jeeves, M., Sridhar, P., …Willcox, B. E. (2017). BTN3A1 Discriminates γδ T Cell Phosphoantigens from Nonantigenic Small Molecules via a Conformational Sensor in Its B30.2 Domain. ACS Chemical Biology, 12(10), 2631-2643. https://doi.org/10.1021/acschembio.7b00694

Journal Article Type Article
Acceptance Date Sep 1, 2017
Online Publication Date Sep 14, 2017
Publication Date Sep 1, 2017
Deposit Date Mar 26, 2019
Publicly Available Date Apr 15, 2019
Journal ACS Chemical Biology
Print ISSN 1554-8929
Electronic ISSN 1554-8937
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 12
Issue 10
Pages 2631-2643
DOI https://doi.org/10.1021/acschembio.7b00694
Related Public URLs http://orca.cf.ac.uk/104312/

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Copyright Statement
This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Chemical Biology, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acschembio.7b00694




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