Structural and functional evidence that Nck interaction with CD3epsilon regulates T-cell receptor activity

J Mol Biol. 2008 Jul 18;380(4):704-16. doi: 10.1016/j.jmb.2008.05.037. Epub 2008 May 22.


Recruitment of signaling molecules to the cytoplasmic domains of the CD3 subunits of the T-cell receptor (TCR) is crucial for early T-cell activation. These transient associations either do or do not require tyrosine phosphorylation of CD3 immune tyrosine activation motifs (ITAMs). Here we show that the non-ITAM-requiring adaptor protein Nck forms a complex with an atypical PxxDY motif of the CD3epsilon tail, which encompasses Tyr166 within the ITAM and a TCR endocytosis signal. As suggested by the structure of the complex, we find that Nck binding inhibits phosphorylation of the CD3epsilon ITAM by Fyn and Lck kinases in vitro. Moreover, the CD3epsilon-Nck interaction downregulates TCR surface expression upon physiological stimulation in mouse primary lymph node cells. This indicates that Nck performs an important regulatory function in T lymphocytes by inhibiting ITAM phosphorylation and/or removing cell surface TCR via CD3epsilon interaction.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Sequence
  • Animals
  • CD3 Complex / chemistry*
  • CD3 Complex / genetics
  • CD3 Complex / metabolism*
  • Humans
  • Mice
  • Molecular Sequence Data
  • Oncogene Proteins / chemistry*
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Peptides / genetics
  • Peptides / metabolism
  • Phosphorylation
  • Protein Binding
  • Proto-Oncogene Proteins c-fyn / antagonists & inhibitors
  • Proto-Oncogene Proteins c-fyn / metabolism
  • Receptor-CD3 Complex, Antigen, T-Cell
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism*
  • Sequence Alignment


  • Adaptor Proteins, Signal Transducing
  • CD3 Complex
  • CD3E protein, human
  • NCK2 protein, human
  • Oncogene Proteins
  • Peptides
  • Receptor-CD3 Complex, Antigen, T-Cell
  • Receptors, Antigen, T-Cell
  • Proto-Oncogene Proteins c-fyn

Associated data

  • PDB/2JXB