Journal article
Critical Roles for Coiled-Coil Dimers of Butyrophilin 3A1 in the Sensing of Prenyl Pyrophosphates by Human V gamma 2V delta 2 T Cells
The Journal of immunology (1950), Vol.203(3), pp.607-626
08/01/2019
DOI: 10.4049/jimmunol.1801252
PMCID: PMC6834341
PMID: 31227581
Abstract
V gamma 2V delta 2 T cells play important roles in human immunity to pathogens and tumors. Their TCRs respond to the sensing of isoprenoid metabolites, such as (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate and isopentenyl pyrophosphate, by butyrophilin (BTN) 3A1. BTN3A1 is an Ig superfamily protein with extracellular IgV/IgC domains and intracellular B30.2 domains that bind prenyl pyrophosphates. We have proposed that intracellular a helices form a coiled-coil dimer that functions as a spacer for the B30.2 domains. To test this, five pairs of anchor residues were mutated to glycine to destabilize the coiled-coil dimer. Despite maintaining surface expression, BTN3A1 mutagenesis either abrogated or decreased stimulation by (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate. BTN3A2 and BTN3A3 proteins and orthologs in alpacas and dolphins are also predicted to have similar coiled-coil dimers. A second short coiled-coil region dimerizes the B30.2 domains. Molecular dynamics simulations predict that mutation of a conserved tryptophan residue in this region will destabilize the dimer, explaining the loss of stimulation by BTN3A1 proteins with this mutation. The juxtamembrane regions of other BTN/BTN-like proteins with B30.2 domains are similarly predicted to assume a helices, with many predicted to form coiled-coil dimers. An exon at the end of this region and the exon encoding the dimerization region for B30.2 domains are highly conserved. We propose that coiled-coil dimers function as rod-like helical molecular spacers to position B30.2 domains, as interaction sites for other proteins, and as dimerization regions to allow sensing by B30.2 domains. In these ways, the coiled-coil domains of BTN3A1 play critical roles for its function.
Details
- Title: Subtitle
- Critical Roles for Coiled-Coil Dimers of Butyrophilin 3A1 in the Sensing of Prenyl Pyrophosphates by Human V gamma 2V delta 2 T Cells
- Creators
- Hong Wang - University of IowaMohanad H. Nada - Iowa City VA Health Care SystemYoshimasa Tanaka - Nagasaki UniversityShun Sakuraba - The University of TokyoCraig T. Morita - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.203(3), pp.607-626
- DOI
- 10.4049/jimmunol.1801252
- PMID
- 31227581
- PMCID
- PMC6834341
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Publisher
- Amer Assoc Immunologists
- Number of pages
- 20
- Grant note
- P30CA086862 / National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) 1 I01 BX000972-01A1 / Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development); US Department of Veterans Affairs University of Iowa Carver College of Medicine Carver Medical Research Initiative Grant I01BX000972 / Veterans Affairs; US Department of Veterans Affairs
- Language
- English
- Date published
- 08/01/2019
- Academic Unit
- Immunology; Internal Medicine
- Record Identifier
- 9984359959102771
Metrics
7 Record Views