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An electrostatic selection mechanism controls sequential kinase signaling downstream of the T cell receptor.

  • Author(s): Shah, Neel H;
  • Wang, Qi;
  • Yan, Qingrong;
  • Karandur, Deepti;
  • Kadlecek, Theresa A;
  • Fallahee, Ian R;
  • Russ, William P;
  • Ranganathan, Rama;
  • Weiss, Arthur;
  • Kuriyan, John
  • et al.
Abstract

The sequence of events that initiates T cell signaling is dictated by the specificities and order of activation of the tyrosine kinases that signal downstream of the T cell receptor. Using a platform that combines exhaustive point-mutagenesis of peptide substrates, bacterial surface-display, cell sorting, and deep sequencing, we have defined the specificities of the first two kinases in this pathway, Lck and ZAP-70, for the T cell receptor ζ chain and the scaffold proteins LAT and SLP-76. We find that ZAP-70 selects its substrates by utilizing an electrostatic mechanism that excludes substrates with positively-charged residues and favors LAT and SLP-76 phosphosites that are surrounded by negatively-charged residues. This mechanism prevents ZAP-70 from phosphorylating its own activation loop, thereby enforcing its strict dependence on Lck for activation. The sequence features in ZAP-70, LAT, and SLP-76 that underlie electrostatic selectivity likely contribute to the specific response of T cells to foreign antigens.

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