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

Neel H. Shah, Qi Wang, Qingrong Yan, Deepti Karandur, Theresa A. Kadlecek, Ian R. Fallahee, William P. Russ, Rama Ranganathan, Arthur Weiss, John Kuriyan

Research output: Contribution to journalArticle

30 Scopus citations

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 surfacedisplay, 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.

Original languageEnglish (US)
Article numbere20105
JournaleLife
Volume5
Issue numberOCTOBER2016
DOIs
StatePublished - Oct 4 2016

    Fingerprint

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Shah, N. H., Wang, Q., Yan, Q., Karandur, D., Kadlecek, T. A., Fallahee, I. R., Russ, W. P., Ranganathan, R., Weiss, A., & Kuriyan, J. (2016). An electrostatic selection mechanism controls sequential kinase signaling downstream of the T cell receptor. eLife, 5(OCTOBER2016), [e20105]. https://doi.org/10.7554/eLife.20105