Molecular Simulations Reveal the Dynamics of the T-Cell Receptor in a T-Cell Model Membrane

Abstract

The T-cell antigen receptor (TCR) initiates immune responses by recognising a wide variety of foreign peptides presented by Major Histocompatibility Complex (MHC) proteins. The TCR consists of non-covalently associated TCRαβ, CD3εγ, CD3εδ and ζζ dimers. The CD3 and ζζ subunits have long intracellular tails that regulate TCR signalling. Despite significant knowledge of the TCR structure and topology, lack of information on the arrangement of its cytoplasmic tails limits our understanding of the molecular mechanism of intracellular signal propagation in a T-cell. In this study, we used molecular modelling to model the entire TCR structure and performed multi-scale molecular dynamics simulations of the TCR embedded in a complex lipid bilayer which mimics the T-cell membrane. Our simulations revealed conformational changes within the transmembrane region of the resting TCR, and also showed that the intracellular signalling tails of CD3 and ζζ subunits fold into an intertwined conformation forming contacts with each other. Additionally, the tails strongly interacted with the inner leaflet of the membrane via cationic stretches, whilst intracellular tyrosine side-chains transiently penetrated into the hydrophobic region of the membrane. Phosphatidyl inositol phosphate (PIP) lipids and cholesterol formed preferential protein-lipid interactions creating a unique local lipid environment around the TCR. Our study provides insights into the TCR's complete structure and dynamics in a membrane in atomic resolution. Further, this potentially forms the basis to study the molecular mechanism of initiation of TCR signalling.