The butyrophilin 3A1 intracellular domain undergoes a conformational change involving the juxtamembrane region.

Khiem Nguyen, Jin Li, Robbins Puthenveetil, Xiaochen Lin, Michael M Poe, Chia-Hung Christine Hsiao, Olga Vinogradova, Andrew J Wiemer

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2017 Nov

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Small isoprenoid diphosphates, such as (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP), are ligands of the internal domain of BTN3A1. Ligand binding in target cells promotes activation of Vγ9Vδ2 T cells. We demonstrate by small-angle X-ray scattering (SAXS) that HMBPP binding to the internal domain of BTN3A1 induces a conformational change in the position of the B30.2 domain relative to the juxtamembrane (JM) region. To better understand the molecular details of this conformational rearrangement, NMR spectroscopy was used to discover that the JM region interacts with HMBPP, specifically at the diphosphate. The spectral location of the affected amide peaks, partial NMR assignments, and JM mutants (ST296AA or T304A) investigated, confirm that the backbone amide of at least one Thr (Thr304), adjacent to conserved Ser, comes close to the HMBPP diphosphate, whereas double mutation of nonconserved residues (Ser/Thr296/297) may perturb the local fold. Cellular mutation of either of the identified Thr residues reduces the activation of Vγ9Vδ2 T cells by HMBPP, zoledronate, and POM2-C-HMBP, but not by a partial agonist BTN3 antibody. Taken together, our results show that ligand binding to BTN3A1 induces a conformational change within the intracellular domain that involves the JM region and is required for full activation.-Nguyen, K., Li, J., Puthenveetil, R., Lin, X., Poe, M. M., Hsiao, C.-H. C., Vinogradova, O., Wiemer, A. J. The butyrophilin 3A1 intracellular domain undergoes a conformational change involving the juxtamembrane region. © FASEB.

Citation

Khiem Nguyen, Jin Li, Robbins Puthenveetil, Xiaochen Lin, Michael M Poe, Chia-Hung Christine Hsiao, Olga Vinogradova, Andrew J Wiemer. The butyrophilin 3A1 intracellular domain undergoes a conformational change involving the juxtamembrane region. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2017 Nov;31(11):4697-4706