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Prakaash, D., Cook, G.P. orcid.org/0000-0003-0223-3652, Acuto, O. et al. (1 more author) (2021) Multi-scale simulations of the T cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region. [Preprint - bioRxiv]
Abstract
The T cell antigen receptor (TCR-CD3) complex initiates T cell activation following recognition of peptides presented by Major Histocompatibility Complex (pMHC)-encoded proteins. The ligation of pMHC to TCRαβ induces Src family kinases activity via the cytoplasmic tails of the CD3δε, CD3γε and ζζ dimers. The TCR-CD3 topology is well understood, but little is known about its conformational dynamics and arrangement of its cytoplasmic tails, limiting our grasp of the signalling mechanism. Here, we investigated the entire TCR-CD3 embedded in an asymmetric lipid bilayer using molecular modelling and multi-scale molecular dynamics simulations. Our study demonstrates conformational changes in the extracellular and transmembrane domains, and the arrangement of the TCR-CD3 cytoplasmic tails. The TCRαβ variable regions were the most flexible in the extracellular domain. The cytoplasmic tails formed highly interlaced structures while some tyrosine sidechains within the immunoreceptor tyrosine-based activation motifs (ITAMs) of the CD3ε and ζ subunits dynamically penetrated the hydrophobic core of the bilayer. Ionic interactions between the cytoplasmic tails and phosphatidylinositol phosphates (PIP2 and PIP3) in the inner leaflet of the lipid bilayer led to the formation of a distinct annular lipid fingerprint around the TCR-CD3 complex. These results combined with available experiential data increase our understanding of the TCR-CD3 activation mechanism and highlight the importance of membrane lipids in regulating T cell activation.
Significance statement The T cell receptor (TCR-CD3) detects antigenic peptides displayed by major histocompatibility complexes (pMHC) to instigate activation of T cell adaptive immunity. Despite significant structural and functional knowledge of TCR-CD3 topology, the membrane interactions and dynamics of its cytoplasmic moieties remain elusive. Interactions of TCR-CD3 cytoplasmic tails with membrane lipids may regulate their phosphorylation by Src-family kinases, the first intracellular event required for T cell activation. Using the static 3D structure of TCR-CD3 resolved by cryo-electron microscopy, we provide novel insights into the protein-lipid interactions of the complete TCR-CD3 embedded in a bilayer closely mimicking its native membrane environment. Our study sheds light on the dynamics of the TCR-CD3 at near-atomic resolution and further aids in deciphering its activation mechanism.
Metadata
Item Type: | Preprint |
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Authors/Creators: |
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Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Medical Research (LIMR) > Division of Haematology and Immunology The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 17 Sep 2024 14:06 |
Last Modified: | 17 Sep 2024 14:34 |
Status: | Published |
Identification Number: | 10.1101/2021.01.11.425722 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:216730 |
Available Versions of this Item
- Multi-scale simulations of the T cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region. (deposited 17 Sep 2024 14:06) [Currently Displayed]