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bioRxiv · 10.1101/2021.11.09.467998

An evolutionary divergent thermodynamic brake in ZAP-70 finetunes the kinetic proofreading in T cell

Gangopadhyay, K.·Roy, A.·Chandradasan, A.·Roy, S.·Debnath, O.·SenGupta, S.·Chowdhury, S.·Das, D.·Das, R.
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Abstract

T cell signaling starts with assembling several tyrosine kinases and adaptor proteins to the T cell receptor (TCR), following the antigen binding. The lifetime of the TCR: antigen complex and the time delay between the recruitment and activation of each kinase determines the T cell response. The mechanism by which the time delays are implemented in TCR signaling is not fully understood. Combining experiments and kinetic modeling, we here report a thermodynamic-brake in the regulatory module of ZAP-70, which determines the ligand selectivity, and may delay the ZAP-70 activation in TCR. Phylogenetic analysis revealed that the evolution of the thermodynamic-brake coincides with the divergence of the adaptive immune system to the cell-mediated and humoral responses. Paralogous kinase Syk expressed in B cells, does not possess such a functional thermodynamic brake, which may explain higher basal activation and lack of ligand selectivity by Syk.

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Gangopadhyay, K., Roy, A., Chandradasan, A., Roy, S., Debnath, O., SenGupta, S., Chowdhury, S., Das, D., Das, R.. 2021-11-10. An evolutionary divergent thermodynamic brake in ZAP-70 finetunes the kinetic proofreading in T cell. https://doi.org/10.1101/2021.11.09.467998

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