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

Xinxin Wang; Scott E Boyken; Jiancheng Hu; Xiaolu Xu; Ryan P Rimer; Madeline A Shea; Andrey S Shaw; Amy H Andreotti; Yina H Huang

doi:10.1126/scisignal.2005147

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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

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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

Xinxin Wang, Scott E Boyken, Jiancheng Hu, Xiaolu Xu, Ryan P Rimer, Madeline A Shea, Andrey S Shaw, Amy H Andreotti and Yina H Huang

Science signaling, Vol.7(337), pp.ra74-ra74

08/05/2014

DOI: 10.1126/scisignal.2005147

PMCID: PMC4269470

PMID: 25097034

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https://lib.dr.iastate.edu/cgi/viewcontent.cgi?article=1198&context=bbmb_ag_pubsView

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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.

Calmodulin - metabolism

Magnetic Resonance Spectroscopy

Protein-Tyrosine Kinases - metabolism

Calcium Signaling - physiology

Mice, Inbred C57BL

CD4-Positive T-Lymphocytes - metabolism

Endoplasmic Reticulum - metabolism

Models, Molecular

Immunoblotting

Protein Structure, Tertiary - genetics

Interleukin-17 - biosynthesis

Animals

Biosynthetic Pathways - genetics

Protein-Tyrosine Kinases - chemistry

Phosphatidylinositols - metabolism

Mice

Calcium Signaling - genetics

Calmodulin - chemistry

Biosynthetic Pathways - physiology

Protein Structure, Tertiary - physiology

Details

Title: Subtitle: Calmodulin and PI(3,4,5)P₃ cooperatively bind to the Itk pleckstrin homology domain to promote efficient calcium signaling and IL-17A production
Creators: Xinxin Wang - Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Scott E Boyken - Department of Biochemistry, Biophysics & Molecular Biology, Iowa State University, Ames, IA 50011, USA
Jiancheng Hu - Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Xiaolu Xu - Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Ryan P Rimer - Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Madeline A Shea - Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA
Andrey S Shaw - Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Amy H Andreotti - Department of Biochemistry, Biophysics & Molecular Biology, Iowa State University, Ames, IA 50011, USA
Yina H Huang - Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Pathology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA. Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA. yina.h.huang@dartmouth.edu
Resource Type: Journal article
Publication Details: Science signaling, Vol.7(337), pp.ra74-ra74
DOI: 10.1126/scisignal.2005147
PMID: 25097034
PMCID: PMC4269470
NLM abbreviation: Sci Signal
ISSN: 1945-0877
eISSN: 1937-9145
Publisher: United States
Grant note: GM057001 / NIGMS NIH HHS R01 AI043957 / NIAID NIH HHS AI043957 / NIAID NIH HHS P30 CA023108 / NCI NIH HHS R01 AI089805 / NIAID NIH HHS AI089805 / NIAID NIH HHS R01 GM057001 / NIGMS NIH HHS
Language: English
Date published: 08/05/2014
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Biochemistry and Molecular Biology
Record Identifier: 9984025284202771

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