title: Membrane-mediated regulation of the intrinsically disordered CD3ϵ cytoplasmic tail of the TCR.
abstract: The regulation of T-cell-mediated immune responses depends on the phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) on T-cell receptors. Although many details of the signaling cascades are well understood, the initial mechanism and regulation of ITAM phosphorylation remains unknown. We used molecular dynamics simulations to study the influence of different compositions of lipid bilayers on the membrane association of the CD3ϵ cytoplasmic tails of the T-cell receptors. Our results show that binding of CD3ϵ to membranes is modulated by both the presence of negatively charged lipids and the lipid order of the membrane. Free-energy calculations reveal that the protein-membrane interaction is favored by the presence of nearby basic residues and the ITAM tyrosines. Phosphorylation minimizes membrane association, rendering the ITAM motif more accessible to binding partners. In systems mimicking biological membranes, the CD3ϵ chain localization is modulated by different facilitator lipids (e.g., gangliosides or phosphoinositols), revealing a plausible regulatory effect on activation through the regulation of lipid composition in cell membranes.
authors.affiliation: Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico.
authors.forename: Cesar A
authors.initials: CA
authors.lastname: López
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut.
authors.forename: Anurag
authors.initials: A
authors.lastname: Sethi
authors.affiliation: Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico.
authors.forename: Byron
authors.initials: B
authors.lastname: Goldstein
authors.affiliation: Department of Pathology and Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
authors.forename: Bridget S
authors.initials: BS
authors.lastname: Wilson
authors.affiliation: Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico; New Mexico Consortium, Los Alamos, New Mexico. Electronic address: gnana@lanl.gov.
authors.forename: S
authors.initials: S
authors.lastname: Gnanakaran
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D005732:Gangliosides / Q000378:metabolism; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry* / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010716:Phosphatidylinositols / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000378:metabolism
chemical_list: D005732:Gangliosides; D064267:Intrinsically Disordered Proteins; D008051:Lipid Bilayers; D010716:Phosphatidylinositols; D011948:Receptors, Antigen, T-Cell