1. Immunology and Inflammation

Structural variability and concerted motions of the T cell receptor - CD3 complex

  1. Prithvi R Pandey
  2. Bartosz Różycki
  3. Reinhard Lipowsky
  4. Thomas R Weikl  Is a corresponding author
  1. Max Planck Institute of Colloids and Interfaces, Germany
  2. Polish Academy of Sciences, Poland
https://doi.org/10.7554/eLife.67195
Share this article
Cite this article
  1. Prithvi R Pandey
  2. Bartosz Różycki
  3. Reinhard Lipowsky
  4. Thomas R Weikl
(2021)
Structural variability and concerted motions of the T cell receptor - CD3 complex
eLife 10:e67195.
https://doi.org/10.7554/eLife.67195
  2. Download BibTeX
  3. Download .RIS

Abstract

We investigate the structural and orientational variability of the membrane-embedded T cell receptor (TCR) - CD3 complex in extensive atomistic molecular dynamics simulations based on the recent cryo-EM structure determined by Dong et al. (2019). We find that the TCR extracellular (EC) domain is highly variable in its orientation by attaining tilt angles relative to the membrane normal that range from 15° to 55°. The tilt angle of the TCR EC domain is both coupled to a rotation of the domain and to characteristic changes throughout the TCR - CD3 complex, in particular in the EC interactions of the C_ FG loop of the TCR, as well as in the orientation of transmembrane helices. The concerted motions of the membrane-embedded TCR - CD3 complex revealed in our simulations provide atomistic insights on conformational changes of the complex in response to tilt-inducing forces on antigen-bound TCRs.

Data availability

All 6000 molecular dynamics structures of the membrane-embedded TCR-CD3 complex used in the analysis have been deposited in the Edmond Open Research Data Repository under https://dx.doi.org/10.17617/3.5m.

The following data sets were generated

Article and author information

Author details

  1. Prithvi R Pandey

    Theory and Bio-Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany
    Competing interests
    The authors declare that no competing interests exist.

  2. Bartosz Różycki

    Institute of Physics, Polish Academy of Sciences, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.

  3. Reinhard Lipowsky

    Theory and Bio-Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8417-8567

  4. Thomas R Weikl

    Theory and Bio-Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany
    For correspondence
    thomas.weikl@mpikg.mpg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0911-5328

Funding

The authors declare that there was no funding for this work.

Reviewing Editor

  1. Michael L Dustin, University of Oxford, United Kingdom

Publication history

  1. Preprint posted: February 3, 2021 (view preprint)
  2. Received: February 3, 2021
  3. Accepted: September 6, 2021
  4. Accepted Manuscript published: September 7, 2021 (version 1)
  5. Version of Record published: October 11, 2021 (version 2)

Copyright

© 2021, Pandey et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 937
    Page views
  • 146
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Prithvi R Pandey
  2. Bartosz Różycki
  3. Reinhard Lipowsky
  4. Thomas R Weikl
(2021)
Structural variability and concerted motions of the T cell receptor - CD3 complex
eLife 10:e67195.
https://doi.org/10.7554/eLife.67195

Categories and tags

Research organism

Further reading

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease

    SARS-CoV-2 host-shutoff impacts innate NK cell functions, but antibody-dependent NK activity is strongly activated through non-spike antibodies

    Ceri Alan Fielding et al.
    Research Article Updated

    The outcome of infection is dependent on the ability of viruses to manipulate the infected cell to evade immunity, and the ability of the immune response to overcome this evasion. Understanding this process is key to understanding pathogenesis, genetic risk factors, and both natural and vaccine-induced immunity. SARS-CoV-2 antagonises the innate interferon response, but whether it manipulates innate cellular immunity is unclear. An unbiased proteomic analysis determined how cell surface protein expression is altered on SARS-CoV-2-infected lung epithelial cells, showing downregulation of activating NK ligands B7-H6, MICA, ULBP2, and Nectin1, with minimal effects on MHC-I. This occurred at the level of protein synthesis, could be mediated by Nsp1 and Nsp14, and correlated with a reduction in NK cell activation. This identifies a novel mechanism by which SARS-CoV-2 host-shutoff antagonises innate immunity. Later in the disease process, strong antibody-dependent NK cell activation (ADNKA) developed. These responses were sustained for at least 6 months in most patients, and led to high levels of pro-inflammatory cytokine production. Depletion of spike-specific antibodies confirmed their dominant role in neutralisation, but these antibodies played only a minor role in ADNKA compared to antibodies to other proteins, including ORF3a, Membrane, and Nucleocapsid. In contrast, ADNKA induced following vaccination was focussed solely on spike, was weaker than ADNKA following natural infection, and was not boosted by the second dose. These insights have important implications for understanding disease progression, vaccine efficacy, and vaccine design.

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease

    Natural Killer Cells: Taking on SARS-CoV-2

    Paola Kučan Brlić, Ilija Brizić
    Insight

    A new study sheds light on how SARS-CoV-2 influences the way natural killer cells can recognize and kill infected cells.

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease

    Domain fusion TLR2-4 enhances the autophagy-dependent clearance of Staphylococcus aureus in the genetic engineering goat

    Mengyao Wang et al.
    Research Article

    Staphylococcus aureus infections pose a potential threat to livestock production and public health. A novel strategy is needed to control S. aureus infections due to its adaptive evolution to antibiotics. Autophagy plays a key role in degrading bacteria for innate immune cells. In order to promote S. aureus clearance via Toll-like receptor (TLR)-induced autophagy pathway, the domain fusion TLR2-4 with the extracellular domain of TLR2, specific recognizing S. aureus, and transmembrane and intracellular domains of TLR4 is assembled, then the goat expressing TLR2-4 is generated. TLR2-4 substantially augments the removal of S. aureus within macrophages by elevating autophagy level. Phosphorylated JNK and ERK1/2 promote LC3-puncta in TLR2-4 macrophages during S. aureus-induced autophagy via MyD88 mediated the TAK1 signaling cascade. Meantime, the TRIF-dependent TBK1-TFEB-OPTN signaling is involved in TLR2-4-triggered autophagy after S. aureus challenge. Moreover, the transcript of ATG5 and ATG12 is significantly increased via cAMP-PKA-NF-κB signaling, which facilitates S. aureus-induced autophagy in TLR2-4 macrophages. Overall, the novel receptor TLR2-4 enhances the autophagy-dependent clearance of S. aureus in macrophages via TAK1/TBK1-JNK/ERK, TBK1-TFEB-OPTN, and cAMP-PKA-NF-κB-ATGs signaling pathways, which provide an alternative approach for resistant against S. aureus infection.