Membrane-Mediated Regulation of the Intrinsically Disordered CD3[epsilon] Cytoplasmic Tail of the TCR

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...

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Bibliographic Details
Published inBiophysical journal Vol. 108; no. 10; p. 2481
Main Authors López, Cesar A, Sethi, Anurag, Goldstein, Byron, Wilson, Bridget S, Gnanakaran, S
Format Journal Article
LanguageEnglish
Published New York Biophysical Society 19.05.2015
Subjects
Cytoplasm
Lipids
Membranes
Phosphorylation
Simulation
T cell receptors
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Summary: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 CD3... cytoplasmic tails of the T-cell receptors. Our results show that binding of CD3... 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 CD3... 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. (ProQuest: ... denotes formulae/symbols omitted.)
ISSN:0006-3495
1542-0086