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Calmodulin and PI(3,4,5)P₃ cooperatively bind to the Itk pleckstrin homology domain to promote efficient calcium signaling and IL-17A production.
- Source :
-
Science signaling [Sci Signal] 2014 Aug 05; Vol. 7 (337), pp. ra74. Date of Electronic Publication: 2014 Aug 05. - Publication Year :
- 2014
-
Abstract
- Precise regulation of the kinetics and magnitude of Ca(2+) signaling enables this signal to mediate diverse responses, such as cell migration, differentiation, vesicular trafficking, and cell death. We showed that the Ca(2+)-binding protein calmodulin (CaM) acted in a positive feedback loop to potentiate Ca(2+) 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 Ca(2+)/CaM and the lipid phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], such that binding to Ca(2+)/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 Ca(2+) 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.<br /> (Copyright © 2014, American Association for the Advancement of Science.)
- Subjects :
- Animals
Biosynthetic Pathways genetics
CD4-Positive T-Lymphocytes metabolism
Calcium Signaling genetics
Calmodulin chemistry
Endoplasmic Reticulum metabolism
Immunoblotting
Magnetic Resonance Spectroscopy
Mice
Mice, Inbred C57BL
Protein Structure, Tertiary genetics
Protein Structure, Tertiary physiology
Protein-Tyrosine Kinases chemistry
Biosynthetic Pathways physiology
Calcium Signaling physiology
Calmodulin metabolism
Interleukin-17 biosynthesis
Models, Molecular
Phosphatidylinositols metabolism
Protein-Tyrosine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1937-9145
- Volume :
- 7
- Issue :
- 337
- Database :
- MEDLINE
- Journal :
- Science signaling
- Publication Type :
- Academic Journal
- Accession number :
- 25097034
- Full Text :
- https://doi.org/10.1126/scisignal.2005147