Campus Units

Biochemistry, Biophysics and Molecular Biology, Roy J. Carver Department of

Document Type

Article

Publication Version

Accepted Manuscript

Publication Date

8-5-2014

Journal or Book Title

Science Signaling

Volume

7

Issue

337

First Page

ra74

DOI

10.1126/scisignal.2005147

Abstract

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. Here, 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.

Comments

This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Signaling on vol. 7 (2014), DOI: 10.1126/scisignal.2005147.

Copyright Owner

American Association for the Advancement of Science

Language

en

File Format

application/pdf

Published Version

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