Weak SLP-76-PLC-γ1 interaction in the LAT-nucleated multi-protein complex fine-tunes TCR signal strength to optimize T cell responsiveness
Yamane, H.; Wada, J.; Stassenko, E. N.; Convertino, N. D.; Lee, M. E.; Vacchio, M. S.; Li, W.; Rathnayake, U. M.; Balagopalan, L.; Chari, R.; Hagenau, H.; Awasthi, P.; McGavern, D.; Bosselut, R.; Samelson, L. E.
Show abstract
Upon TCR engagement several protein tyrosine kinases are recruited and activated, and adapter proteins and enzymes are phosphorylated on tyrosine residues, leading to further events characterizing activated T cells. Phosphorylation of the LAT adapter protein enables binding of the enzyme PLC-{gamma}1 and of a dimer of two additional adapter proteins Gads and SLP-76, forming a tetrameric structure. Within this heterotetramer there is a weak interaction between SLP-76 and PLC-{gamma}1, and the relevant binding sites of SLP-76 and PLC-{gamma}1 are highly conserved in vertebrates. To address the biological relevance of this weak interaction, we introduced a mutation in the SLP-76 that enhanced its affinity for PLC-{gamma}1 and found that this mutation increased PLC-{gamma}1 activity and altered thymocyte development and peripheral T cell responses due to enhanced TCR signal strength. The conserved weak SLP-76-PLC-{gamma}1 interaction is critical for the controlled activation of PLC-{gamma}1, thus fine-tuning TCR signal strength to optimize T cell-mediated immunity.
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