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

Neel H ShahQi WangQingrong YanDeepti KarandurTheresa A KadlecekIan R FallaheeWilliam P RussRama RanganathanArthur WeissJohn Kuriyan
Published in: eLife (2016)
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.
Keyphrases
  • single cell
  • molecular dynamics simulations
  • stem cells
  • cell therapy
  • mouse model
  • mesenchymal stem cells
  • dendritic cells
  • tyrosine kinase