Loading…
An evolutionary divergent thermodynamic brake in ZAP-70 fine-tunes the kinetic proofreading in T cells
T cell signaling starts with assembling several tyrosine kinases and adapter proteins to the T cell receptor (TCR), following the antigen binding to the TCR. The stability of the TCR–antigen complex and the delay between the recruitment and activation of each kinase determines the T cell response. I...
Saved in:
Published in: | The Journal of biological chemistry 2022-10, Vol.298 (10), p.102376-102376, Article 102376 |
---|---|
Main Authors: | , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Summary: | T cell signaling starts with assembling several tyrosine kinases and adapter proteins to the T cell receptor (TCR), following the antigen binding to the TCR. The stability of the TCR–antigen complex and the delay between the recruitment and activation of each kinase determines the T cell response. Integration of such delays constitutes a kinetic proofreading mechanism to regulate T cell response to the antigen binding. However, the mechanism of these delays is not fully understood. Combining biochemical experiments and kinetic modeling, here we report a thermodynamic brake in the regulatory module of the tyrosine kinase ZAP-70, which determines the ligand selectivity, and may delay the ZAP-70 activation upon antigen binding to TCR. The regulatory module of ZAP-70 comprises of a tandem SH2 domain that binds to its ligand, doubly-phosphorylated ITAM peptide (ITAM-Y2P), in two kinetic steps: a fast step and a slow step. We show the initial encounter complex formation between the ITAM-Y2P and tandem SH2 domain follows a fast-kinetic step, whereas the conformational transition to the holo-state follows a slow-kinetic step. We further observed a thermodynamic penalty imposed during the second phosphate-binding event reduces the rate of structural transition to the holo-state. Phylogenetic analysis revealed the evolution of the thermodynamic brake coincides with the divergence of the adaptive immune system to the cell-mediated and humoral responses. In addition, the paralogous kinase Syk expressed in B cells does not possess such a functional thermodynamic brake, which may explain the higher basal activation and lack of ligand selectivity in Syk. |
---|---|
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1016/j.jbc.2022.102376 |