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

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 d...

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Bibliographic Details
Published in:The FASEB journal 2017-11, Vol.31 (11), p.4697-4706
Main Authors: Nguyen, Khiem, Li, Jin, Puthenveetil, Robbins, Lin, Xiaochen, Poe, Michael M., Christine Hsiao, Chia‐Hung, Vinogradova, Olga, Wiemer, Andrew J.
Format: Article
Language:English
Subjects:
Amino Acid Substitution
Antigens, CD - chemistry
Antigens, CD - genetics
Antigens, CD - metabolism
B7 family coreceptor
Binding
bisphosphonate
Butyrophilin
Butyrophilins - chemistry
Butyrophilins - genetics
Butyrophilins - metabolism
CD277
Cell activation
Crystal structure
Diphosphates
Humans
Intracellular
K562 Cells
Ligands
Lymphocytes
Lymphocytes T
Magnetic resonance spectroscopy
Mutants
Mutation
Mutation, Missense
NMR
NMR spectroscopy
Nuclear magnetic resonance
Nuclear Magnetic Resonance, Biomolecular
Organophosphates - chemistry
Organophosphates - metabolism
phosphoantigen
Protein Domains
Residues
Small angle X ray scattering
X-Ray Diffraction
X-ray scattering
Zoledronic acid
γ δ T cell
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Summary: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 (ST296 AA or T304 A) 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 J. 31, 4697–4706 (2017). www.fasebj.org
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.201601370RR