5HM7

The Intracellular domain of Butyrophilin 3A1 protein

Summary for 5HM7

• Entry DOI: 10.2210/pdb5hm7/pdb
• Descriptor: Butyrophilin subfamily 3 member A1, GLYCEROL, BETA-MERCAPTOETHANOL, ... (5 entities in total)
• Functional Keywords: immunological protein, intracellular domain, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 57888.65

Authors

Adams, E.J.,Gu, S. (deposition date: 2016-01-15, release date: 2017-07-26, Last modification date: 2023-09-27)

Primary citation

Gu, S.,Sachleben, J.R.,Boughter, C.T.,Nawrocka, W.I.,Borowska, M.T.,Tarrasch, J.T.,Skiniotis, G.,Roux, B.,Adams, E.J.
Phosphoantigen-induced conformational change of butyrophilin 3A1 (BTN3A1) and its implication on V gamma 9V delta 2 T cell activation.
Proc. Natl. Acad. Sci. U.S.A., 114:E7311-E7320, 2017

PubMed Abstract: Human Vγ9Vδ2 T cells respond to microbial infections as well as certain types of tumors. The key initiators of Vγ9Vδ2 activation are small, pyrophosphate-containing molecules called phosphoantigens (pAgs) that are present in infected cells or accumulate intracellularly in certain tumor cells. Recent studies demonstrate that initiation of the Vγ9Vδ2 T cell response begins with sensing of pAg via the intracellular domain of the butyrophilin 3A1 (BTN3A1) molecule. However, it is unknown how downstream events can ultimately lead to T cell activation. Here, using NMR spectrometry and molecular dynamics (MD) simulations, we characterize a global conformational change in the B30.2 intracellular domain of BTN3A1 induced by pAg binding. We also reveal by crystallography two distinct dimer interfaces in the BTN3A1 full-length intracellular domain, which are stable in MD simulations. These interfaces lie in close proximity to the pAg-binding pocket and contain clusters of residues that experience major changes of chemical environment upon pAg binding. This suggests that pAg binding disrupts a preexisting conformation of the BTN3A1 intracellular domain. Using a combination of biochemical, structural, and cellular approaches we demonstrate that the extracellular domains of BTN3A1 adopt a V-shaped conformation at rest, and that locking them in this resting conformation without perturbing their membrane reorganization properties diminishes pAg-induced T cell activation. Based on these results, we propose a model in which a conformational change in BTN3A1 is a key event of pAg sensing that ultimately leads to T cell activation.

PubMed: 28807997
DOI: 10.1073/pnas.1707547114

Experimental method

X-RAY DIFFRACTION (1.93 Å)