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T cell receptor dwell-times control the kinase activity of ZAP-70
  • Published Date:
    Aug 03 2015
  • Source:
    Nat Immunol. 16(9):961-969.
Filetype[PDF-1.38 MB]

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  • Description:
    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.

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  • Funding:
    1DP2GM105455-01/DP/NCCDPHP CDC HHS/United States
    CA014195/CA/NCI NIH HHS/United States
    DP2 GM105455/GM/NIGMS NIH HHS/United States
    R01 GM110397/GM/NIGMS NIH HHS/United States
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