An electrostatic selection mechanism controls sequential kinase signaling downstream of the T cell receptor
- Howard Hughes Medical Institute, University of California, Berkeley, United States
- D. E. Shaw Research, United States
- Janssen Pharmaceutical Companies of Johnson and Johnson, United States
- Howard Hughes Medical Institute, University of California, San Francisco, United States
- University of Texas Southwestern Medical Center, United States
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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Author details
Funding
National Institutes of Health (PO1 AI091580)
- Arthur Weiss
- John Kuriyan
Damon Runyon Cancer Research Foundation
- Neel H Shah
Cancer Research Institute
- Qi Wang
- Qingrong Yan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2016, Shah et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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An electrostatic selection mechanism controls sequential kinase signaling downstream of the T cell receptor
eLife 5:e20105.
https://doi.org/10.7554/eLife.20105
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