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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Precise regulation of the kinetics and magnitude of Ca2+ signaling enables this signal to mediate diverse responses, such as cell migration, differentiation, vesicular trafficking, and cell death. We showed that the Ca2+-binding protein calmodulin (CaM) acted in a positive feedback loop to potentiate Ca2+ signaling downstream of the Tec kinase family member Itk. Using NMR (nuclear magnetic resonance), we mapped CaM binding to two loops adjacent to the lipid-binding pocket within the Itk pleckstrin homology (PH) domain. The Itk PH domain bound synergistically to Ca2+/CaM and the lipid phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], such that binding to Ca2+/CaM enhanced the binding to PI(3,4,5)P3 and vice versa. Disruption of CaM binding attenuated Itk recruitment to the membrane and diminished release of Ca2+ from the endoplasmic reticulum. Moreover, disruption of this feedback loop abrogated Itk-dependent production of the proinflammatory cytokine IL-17A (interleukin-17A) by CD4+ T cells. Additionally, we found that CaM associated with PH domains from other proteins, indicating that CaM may regulate other PH domain–containing proteins.

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