Journal
ACS CHEMICAL BIOLOGY
Volume 12, Issue 10, Pages 2631-2643Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.7b00694
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Funding
- Wellcome Trust [364 099266/Z/12/Z]
- Wellcome Trust [106292/Z/14/Z] Funding Source: Wellcome Trust
- BBSRC [BB/P009840/1] Funding Source: UKRI
- The Francis Crick Institute [10093] Funding Source: researchfish
- Wellcome Trust [106292/Z/14/Z] Funding Source: researchfish
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Human V gamma 9/V delta 2 T-cells detect tumor cells and microbial infections by recognizing 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 V gamma 9/V delta 2 T-cells; however, the molecular mechanisms involved in BTN3A1-mediated metabolite sensing are unclear, including how P-Ag's are discriminated from nonantigenic small molecules. Here, we utilized 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 nonantigenic 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 V gamma 9/V delta 2-based T-cell immunotherapies.
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