Regulation of T cell receptor activation by dynamic membrane binding of the CD3epsilon cytoplasmic tyrosine-based motif

Cell. 2008 Nov 14;135(4):702-13. doi: 10.1016/j.cell.2008.09.044.


Many immune system receptors signal through cytoplasmic tyrosine-based motifs (ITAMs), but how receptor ligation results in ITAM phosphorylation remains unknown. Live-cell imaging studies showed a close interaction of the CD3epsilon cytoplasmic domain of the T cell receptor (TCR) with the plasma membrane through fluorescence resonance energy transfer between a C-terminal fluorescent protein and a membrane fluorophore. Electrostatic interactions between basic CD3epsilon residues and acidic phospholipids enriched in the inner leaflet of the plasma membrane were required for binding. The nuclear magnetic resonance structure of the lipid-bound state of this cytoplasmic domain revealed deep insertion of the two key tyrosines into the hydrophobic core of the lipid bilayer. Receptor ligation thus needs to result in unbinding of the CD3epsilon ITAM from the membrane to render these tyrosines accessible to Src kinases. Sequestration of key tyrosines into the lipid bilayer represents a previously unrecognized mechanism for control of receptor activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • CD3 Complex / metabolism*
  • Cell Membrane / metabolism*
  • Cytoplasm / metabolism
  • Fluorescence Resonance Energy Transfer
  • Lipid Bilayers / chemistry
  • Lipids / chemistry
  • Magnetic Resonance Spectroscopy
  • Models, Biological
  • Molecular Sequence Data
  • Protein Binding
  • Receptors, Antigen, T-Cell / metabolism*
  • Tyrosine / chemistry*
  • src-Family Kinases / metabolism


  • CD3 Complex
  • CD3E protein, human
  • Lipid Bilayers
  • Lipids
  • Receptors, Antigen, T-Cell
  • Tyrosine
  • src-Family Kinases

Associated data

  • PDB/2K4F