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CRYSTAL STRUCTURE OF INTRACELLULAR B30.2 DOMAIN OF BTN3A1 BOUND TO CITRATE
Structural highlights
FunctionBT3A1_HUMAN Plays a role in T-cell activation and in the adaptive immune response. Regulates the proliferation of activated T-cells. Regulates the release of cytokines and IFNG by activated T-cells. Mediates the response of T-cells toward infected and transformed cells that are characterized by high levels of phosphorylated metabolites, such as isopentenyl pyrophosphate.[1] [2] [3] [4] Publication Abstract from PubMedHuman Vgamma9/Vdelta2 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 Vgamma9/Vdelta2 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 Vgamma9/Vdelta2 -based T-cell immunotherapies. BTN3A1 discriminates gammadelta T cell phosphoantigens from non-antigenic small molecules via a conformational sensor in its B30.2 domain.,Salim M, Knowles TJ, Baker AT, Davey MS, Jeeves M, Sridhar P, Wilkie J, Willcox CR, Kadri H, Taher TE, Vantourout P, Hayday A, Mehellou Y, Mohammed F, Willcox BE ACS Chem Biol. 2017 Sep 1. doi: 10.1021/acschembio.7b00694. PMID:28862425[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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