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

eLife

Rama Ranganathan¹  Qi Wang¹  Theresa A Kadlecek¹  Ian R Fallahee²  Arthur Weiss²  Qingrong Yan²  Neel H Shah³  William P Russ³  John Kuriyan³  Deepti Karandur³ 

[1] California Institute for Quantitative Biosciences, University of California, Berkeley, United States;Howard Hughes Medical Institute, University of California, Berkeley, United States;Department of Molecular and Cell Biology, University of California, Berkeley, United States;

关键词: tyrosine kinase;    T cell receptor;    ZAP-70;    LAT;    Lck;    bacterial surface display;   

DOI  :  10.7554/eLife.20105

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown