Structural basis and energy landscape for the Ca2+ gating and calmodulation of the Kv7.2 K+ channel

Proceedings of the National Academy of Sciences of the United States of America
Ganeko Bernardo-SeisdedosOscar Millet

Abstract

The Kv7.2 (KCNQ2) channel is the principal molecular component of the slow voltage-gated, noninactivating K+ M-current, a key controller of neuronal excitability. To investigate the calmodulin (CaM)-mediated Ca2+ gating of the channel, we used NMR spectroscopy to structurally and dynamically describe the association of helices hA and hB of Kv7.2 with CaM, as a function of Ca2+ concentration. The structures of the CaM/Kv7.2-hAB complex at two different calcification states are reported here. In the presence of a basal cytosolic Ca2+ concentration (10-100 nM), only the N-lobe of CaM is Ca2+-loaded and the complex (representative of the open channel) exhibits collective dynamics on the millisecond time scale toward a low-populated excited state (1.5%) that corresponds to the inactive state of the channel. In response to a chemical or electrical signal, intracellular Ca2+ levels rise up to 1-10 μM, triggering Ca2+ association with the C-lobe. The associated conformational rearrangement is the key biological signal that shifts populations to the closed/inactive channel. This reorientation affects the C-lobe of CaM and both helices in Kv7.2, allosterically transducing the information from the Ca2+-binding site to the transmembrane re...Continue Reading

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Citations

Jul 20, 2018·Biomolecules·Alessandro Alaimo, Alvaro Villarroel
Sep 26, 2019·Current Protein & Peptide Science·Zsolt Dürvanger, Veronika Harmat
Jul 31, 2020·Proceedings of the National Academy of Sciences of the United States of America·Gabriel OrtegaKevin W Plaxco
Sep 5, 2020·Cell Research·Xiaoxiao LiJiangtao Guo
May 21, 2020·Frontiers in Pharmacology·Kathryn R BrewerCharles R Sanders
Jun 27, 2020·International Journal of Molecular Sciences·Pedro A LazoCarmen Fons
Feb 23, 2020·International Journal of Molecular Sciences·Eider NúñezAlvaro Villarroel
Jan 24, 2019·International Journal of Molecular Sciences·Janire UrrutiaAlvaro Villarroel
Feb 9, 2021·Frontiers in Physiology·Wenhui Zhuang, Zhiqiang Yan
Mar 7, 2021·International Journal of Molecular Sciences·Jon Gil-MartínezOscar Millet
Nov 1, 2020·Current Opinion in Structural Biology·Luca UnioneOscar Millet
May 23, 2021·BMC Biology·Janire UrrutiaAlvaro Villarroel

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Methods Mentioned

BETA
X-ray
NMR
Size exclusion chromatography
FRET
fluorescence

Software Mentioned

pCLAMP
SigmaPlot

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