A Calmodulin C-Lobe Ca2+-Dependent Switch Governs Kv7 Channel Function
Copyright policy )A Calmodulin C-Lobe Ca2+-Dependent Switch Governs Kv7 Channel Function
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.
- University of California, San Francisco United States
- Lawrence Berkeley National Laboratory United States
- California Institute for Biomedical Research United States
570, Protein Structure, calmodulin, 1.1 Normal biological development and functioning, Medical Physiology, 610, Crystallography, X-Ray, KCNQ3 Potassium Channel, KCNQ, Calmodulin, 2.1 Biological and endogenous factors, Psychology, Humans, KCNQ2 Potassium Channel, Protein Isoforms, X-ray crystallography, Crystallography, Neurology & Neurosurgery, Binding Sites, Biomedical and Clinical Sciences, KCNQ Potassium Channels, Neurosciences, electrophysiology, isothermal titration calorimetry, Protein Structure, Tertiary, HEK293 Cells, Kv7 channel, small-angle X-ray scattering, KCNQ1 Potassium Channel, X-Ray, Biological psychology, Cognitive Sciences, Calcium, Generic health relevance, Tertiary, Protein Binding
570, Protein Structure, calmodulin, 1.1 Normal biological development and functioning, Medical Physiology, 610, Crystallography, X-Ray, KCNQ3 Potassium Channel, KCNQ, Calmodulin, 2.1 Biological and endogenous factors, Psychology, Humans, KCNQ2 Potassium Channel, Protein Isoforms, X-ray crystallography, Crystallography, Neurology & Neurosurgery, Binding Sites, Biomedical and Clinical Sciences, KCNQ Potassium Channels, Neurosciences, electrophysiology, isothermal titration calorimetry, Protein Structure, Tertiary, HEK293 Cells, Kv7 channel, small-angle X-ray scattering, KCNQ1 Potassium Channel, X-Ray, Biological psychology, Cognitive Sciences, Calcium, Generic health relevance, Tertiary, Protein Binding
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