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Neuron. 2018 Feb 21;97(4):836-852.e6. doi: 10.1016/j.neuron.2018.01.035. Epub 2018 Feb 8.

A Calmodulin C-Lobe Ca2+-Dependent Switch Governs Kv7 Channel Function.

Author information

1
Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94158, USA.
2
Molecular Biophysics and Integrated Bio-imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
3
Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94158, USA; Molecular Biophysics and Integrated Bio-imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Departments of Biochemistry and Biophysics, and Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA; California Institute for Quantitative Biomedical Research, University of California San Francisco, San Francisco, CA 94158, USA; Kavli Institute for Fundamental Neuroscience, University of California San Francisco, San Francisco, CA 94158, USA. Electronic address: daniel.minor@ucsf.edu.

Abstract

Kv7 (KCNQ) voltage-gated potassium channels control excitability in the brain, heart, and ear. Calmodulin (CaM) is crucial for Kv7 function, but how this calcium sensor affects activity has remained unclear. Here, we present X-ray crystallographic analysis of CaM:Kv7.4 and CaM:Kv7.5 AB domain complexes that reveal an Apo/CaM clamp conformation and calcium binding preferences. These structures, combined with small-angle X-ray scattering, biochemical, and functional studies, establish a regulatory mechanism for Kv7 CaM modulation based on a common architecture in which a CaM C-lobe calcium-dependent switch releases a shared Apo/CaM clamp conformation. This C-lobe switch inhibits voltage-dependent activation of Kv7.4 and Kv7.5 but facilitates Kv7.1, demonstrating that mechanism is shared by Kv7 isoforms despite the different directions of CaM modulation. Our findings provide a unified framework for understanding how CaM controls different Kv7 isoforms and highlight the role of membrane proximal domains for controlling voltage-gated channel function. VIDEO ABSTRACT.

KEYWORDS:

KCNQ; Kv7 channel; X-ray crystallography; calmodulin; electrophysiology; isothermal titration calorimetry; small-angle X-ray scattering

PMID:
29429937
PMCID:
PMC5823783
DOI:
10.1016/j.neuron.2018.01.035
[Indexed for MEDLINE]
Free PMC Article

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