T cell receptor dwell times control the kinase activity of Zap70

• Published in: Nature immunology Vol. 16; no. 9; pp. 961 - 969
• Main Authors: Klammt, Christian, Novotná, Lucie, Li, Dongyang T, Wolf, Miriam, Blount, Amy, Zhang, Kai, Fitchett, Jonathan R, Lillemeier, Björn F
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.09.2015
• Subjects: CD3 Complex - metabolism; Cell Membrane - metabolism; Cell receptors; Deuterium Exchange Measurement; Enzymes; Genetic aspects; Genetic research; Humans; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism; Mass Spectrometry; Molecular Dynamics Simulation; Mutation; Phosphorylation; Phosphotransferases; Properties; Protein Binding; Protein Structure, Tertiary; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Regulation; Structural analysis; T cells; Time Factors; ZAP-70 Protein-Tyrosine Kinase - genetics; ZAP-70 Protein-Tyrosine Kinase - metabolism
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.3231

Kinase recruitment to membrane receptors is essential for signal transduction. However, the underlying regulatory mechanisms are poorly understood. We investigated how conformational changes control T cell receptor (TCR) association and activity of the kinase Zap70. Structural analysis showed that TCR binding or phosphorylation of Zap70 triggers a transition from a closed, autoinhibited conformation to an open conformation. Using Zap70 mutants with defined conformations, we found that TCR dwell times controlled Zap70 activity. The closed conformation minimized TCR dwell times and thereby prevented activation by membrane-associated kinases. Parallel recruitment of coreceptor-associated Lck kinase to the TCR ensured Zap70 phosphorylation and stabilized Zap70 TCR binding. Our study suggests that the dynamics of cytosolic enzyme recruitment to the plasma membrane regulate the activity and function of receptors lacking intrinsic catalytic activity.