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BTN3A1 discriminates γδ T cell phosphoantigens from non-antigenic small molecules via a conformational sensor in its B30.2 domain

DOI: 10.1021/acschembio.7b00694 DOI Help

Authors: Mahboob Salim (University of Birmingham) , Timothy J. Knowles (University of Birmingham) , Alfie T. Baker (University of Birmingham) , Martin S. Davey (University of Birmingham) , Mark Jeeves (University of Birmingham) , Pooja Sridhar (University of Birmingham) , John Wilkie (University of Birmingham) , Carrie R. Willcox (University of Birmingham) , Hachemi Kadri (Cardiff University) , Taher E. Taher (University of Birmingham) , Pierre Vantourout (King's College London) , Adrian Hayday (King's College London) , Youcef Mehellou (Cardiff University) , Fiyaz Mohammed (University of Birmingham) , Benjamin E. Willcox (University of Birmingham)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Chemical Biology

State: Published (Approved)
Published: September 2017
Diamond Proposal Number(s): 14692

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.

Journal Keywords: Butyrophilin; phosphoantigen; B30.2; conformational change; γδ T cell receptor; P-Ag (phosphoantigens)

Diamond Keywords: Immunotherapy

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 04/09/2017 09:17

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Health & Wellbeing Structural biology Biophysics Drug Discovery Life Sciences & Biotech

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