Molecular Mechanism of Interfacial Adsorption of Disordered Cytoplasmic Tail of Immune Receptors to Membrane

Abstract

Important immune responses are linked to Src-mediated phosphorylation of cytoplasmic tyrosine-based motifs (ITAMs). However, the mechanism of how receptor ligation translates into ITAM phosphorylation remains elusive. Here, we use molecular dynamic simulations to explore the potential regulatory involvement of lipid membranes and their influence on the structure and behavior of the cytoplasmic portion of the CD3ɛ chain of the T-cell receptor. It has been hypothesized that the accessibility of ITAM motifs, such as those in the CD3ɛ cytoplasmic tail, can be blocked by ionic interactions between positively charged amino acids in receptor tails and negatively charged lipid head groups. This interesting hypothesis represents a previously unrecognized mechanism for control of receptor activation. Our simulations support the notion that the net charge of the lipids present in the membrane can affect peptide-membrane interactions. Results are consistent with experimental findings that show increase interfacial absorption in negatively charged lipid bilayer. Our simulations revealed the conformational variability of the disordered tail, which led to an additional focus on quantifying the interaction by free energy calculations, combined with long time-scale simulations using coarse-grained (CG) approaches. These studies will be extended to address how changes in ionic conditions can modulate phosphorylation of ITAM motifs and lead to regulation of activation of the TCR and other ITAM-bearing immunoreceptors.