4 years ago

The T-Cell Receptor Can Bind to the Peptide-Bound Major Histocompatibility Complex and Uncomplexed β2-Microglobulin through Distinct Binding Sites

The T-Cell Receptor Can Bind to the Peptide-Bound Major Histocompatibility Complex and Uncomplexed β2-Microglobulin through Distinct Binding Sites
Kasper D. Rand, Michel A. Cuendet, Immanuel Luescher, Kirsten Scholten, Patrick S. Merkle, George Coukos, Olivier Michielin, Mathias Ferber, Thomas J. D. Jørgensen, Song Hongjian, Vincent Zoete, Melita Irving
T-Cell receptor (TCR)-mediated recognition of the peptide-bound major histocompatibility complex (pMHC) initiates an adaptive immune response against antigen-presenting target cells. The recognition events take place at the TCR–pMHC interface, and their effects on TCR conformation and dynamics are controversial. Here, we have measured the time-resolved hydrogen/deuterium exchange (HDX) of a soluble TCR in the presence and absence of its cognate pMHC by mass spectrometry to delineate the impact of pMHC binding on solution-phase structural dynamics in the TCR. Our results demonstrate that while TCR–pMHC complex formation significantly stabilizes distinct CDR loops of the TCR, it does not trigger structural changes in receptor segments remote from the binding interface. Intriguingly, our HDX measurements reveal that the TCR α-constant domain (C- and F-strand) directly interacts with the unbound MHC light chain, β2-microglobulin (β2m). Surface plasmon resonance measurements corroborated a binding event between TCR and β2m with a dissociation constant of 167 ± 20 μM. We propose a model structure for the TCR−β2m complex based on a refined protein–protein docking approach driven by HDX data and information from molecular dynamics simulations. Using a biological assay based on TCR gene-engineered primary human T cells, we did not observe a significant effect of β2m on T-cell cytotoxicity, suggesting an alternate role for β2m binding. Overall, we show that binding of β2m to the TCR occurs in vitro and, as such, not only should be considered in structure–function studies of the TCR–pMHC complex but also could play a hitherto unidentified role in T-cell function in vivo.

Publisher URL: http://dx.doi.org/10.1021/acs.biochem.7b00385

DOI: 10.1021/acs.biochem.7b00385

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.