Structural and functional evidence that Nck interaction with CD3epsilon regulates T-cell receptor activity.
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.
Takeuchi
Koh
K
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
Yang
Hailin
H
Ng
Elise
E
Park
Sungh-youk
SY
Sun
Zhen-Yu J
ZY
Reinherz
Ellis L
EL
Wagner
Gerhard
G
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D017252:CD3 Complex / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors / Q000378:metabolism; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment
D048868:Adaptor Proteins, Signal Transducing; D017252:CD3 Complex; C115335:CD3E protein, human; C485544:NCK2 protein, human; D015513:Oncogene Proteins; D010455:Peptides; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011948:Receptors, Antigen, T-Cell; D051076:Proto-Oncogene Proteins c-fyn