Research ArticleImmunology

Calmodulin and PI(3,4,5)P3 cooperatively bind to the Itk pleckstrin homology domain to promote efficient calcium signaling and IL-17A production

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Sci. Signal.  05 Aug 2014:
Vol. 7, Issue 337, pp. ra74
DOI: 10.1126/scisignal.2005147

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Two Signals Are Better Than One

Lipid binding to pleckstrin homology (PH) domains enables spatial and temporal control of protein activity. T cell activation is a highly localized event and involves calcium signals and PH domain–containing kinases, such as Itk. Wang et al. report that calcium and lipids converged at Itk, creating a positive feedback loop necessary for full T cell activation. Nuclear magnetic resonance (NMR) analysis revealed that the PH domain of Itk interacted with the calcium-binding protein calmodulin and with PI(3,4,5)P3 and that the two enhanced each other’s binding to the PH domain. Both interactions were required for maximal production of the proinflammatory cytokine IL-17A. Furthermore, calmodulin binding occurred with several other PH domains, suggesting that responding to calcium signaling may be a common function of this domain.