Histidine phosphorylation relieves copper inhibition in the mammalian potassium channel KCa3.1
- Kimmel Center for Biology and Medicine at the Skirball Institute, United States
- Salk Institute for Biological Studies, United States
- Duke University School of Medicine, United States
Abstract
KCa2.1, KCa2.2, KCa2.3, and KCa3.1 constitute a family of mammalian small- to intermediate-conductance potassium channels that are activated by calcium-calmodulin. KCa3.1 is unique among these four channels in that activation requires, in addition to calcium, phosphorylation of a single histidine residue (His358) in the cytoplasmic region, by nucleoside diphosphate kinase-B (NPDK-B). The mechanism by which KCa3.1 is activated by histidine phosphorylation is unknown. Histidine phosphorylation is well characterized in prokaryotes but poorly understood in eukaryotes. Here we demonstrate that phosphorylation of His358 activates KCa3.1 by antagonizing copper-mediated inhibition of the channel. Furthermore, we show that activated CD4+ T cells deficient in intracellular copper exhibit increased KCa3.1 histidine phosphorylation and channel activity, leading to increased calcium flux and cytokine production. These findings reveal a novel regulatory mechanism for a mammalian potassium channel and for T-cell activation, and highlight a unique feature of histidine versus serine/threonine and tyrosine as a regulatory phosphorylation site.
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Funding
National Institute of Allergy and Infectious Diseases (R21AI107443)
- Stevan R Hubbard
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK074192)
- Dennis J Thiele
National Institute of General Medical Sciences (R01GM084195)
- Edward Y Skolnik
National Cancer Institute (R01CA194584)
- Tony Hunter
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2016, Srivastava et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Histidine phosphorylation relieves copper inhibition in the mammalian potassium channel KCa3.1
eLife 5:e16093.
https://doi.org/10.7554/eLife.16093
