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BTN3A1 discriminates γδ T cell phosphoantigens from non-antigenic 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 ORCID: https://orcid.org/0000-0001-5720-8513, Mohammed, Fiyaz and Willcox, Benjamin E. 2017. BTN3A1 discriminates γδ T cell phosphoantigens from non-antigenic small molecules via a conformational sensor in its B30.2 domain. ACS Chemical Biology 12 (10) , pp. 2631-2643. 10.1021/acschembio.7b00694

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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 negatively-charged 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: American Chemical Society
ISSN: 1554-8929
Date of First Compliant Deposit: 4 September 2017
Date of Acceptance: 1 September 2017
Last Modified: 07 Nov 2023 08:32
URI: https://orca.cardiff.ac.uk/id/eprint/104312

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