Elucidating the T Cell Receptor Transmembrane Organization via Multi-Scale Molecular Dynamics Simulations

Abstract

The T cell antigen receptor (TCR) plays a key role in the adaptive immunity of all vertebrates. It is able to identify with high sensitivity, specificity and rapidity peptide antigens from invading microbial pathogens presented by MHC proteins (peptide-MHC) and signals via multiple intracellular pathways to prepare adequate countermeasures to fend them off. The TCR has a complex structural organization consisting of the TCR αβ heterodimer, which recognizes peptide-MHC, and it is non-covalently associated with three dimers (the CD3 eγ, eδ and ζζ) that regulate signal transduction. Despite advances in the field, the topology of TCR-CD3 subunit organization is still largely hypothetical. Molecular dynamics simulations can now be applied with confidence to study the assembly of transmembrane (TM) segments of membrane proteins in model lipid bilayers. In this study we probe the assembly of the TCR αβ TM heterodimer and its interactions with the CD3 accessory subunits at both atomistic and coarse-grained resolution using a multi-scale simulation approach. Our results suggest a dynamic structural model for the TCR αβ TM complex and how it associates with the CD3 ζζ subunit. Additionally, the interaction of the TCR with its lipid environment may also regulate the organization of the TCR-CD3 TM complex. We will also discuss simulation of the TCR TM region in complex lipid bilayers that resemble plasma membranes. Our results suggest preferential interactions of the TCR TM region with cholesterol and anionic lipids in the bilayer.