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Structural basis and energy landscape for the Ca2+ gating and calmodulation of the Kv7.2 K+ channel
- Source :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Year :
- 2018
- Publisher :
- National Academy of Sciences, 2018.
-
Abstract
- Significance Ion channels are sophisticated proteins that exert control over a plethora of body functions. Specifically, the members of the Kv7 family are prominent components of the nervous systems, responsible for the ion fluxes that regulate the electrical signaling in neurons and cardiac myocytes. Albeit its relevance, there are still several questions, including the Ca2+/calmodulin (CaM)-mediated gating mechanism. We found that Ca2+ binding to CaM triggers a segmental rotation that allosterically transmits the signal from the cytosol up to the transmembrane region. NMR-derived analysis of the dynamics demonstrates that it occurs through a conformational selection mechanism. Energetically, CaM association with the channel tunes the affinities of the CaM lobes (calmodulation) so that the channel can sense the specific changes in [Ca2+] resulting after an action potential.<br />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 region of the channel.
- Subjects :
- 0301 basic medicine
calmodulin
Multidisciplinary
Calmodulin
biology
Chemistry
Energy landscape
Gating
Nuclear magnetic resonance spectroscopy
Biological Sciences
03 medical and health sciences
Biophysics and Computational Biology
030104 developmental biology
0302 clinical medicine
Protein structure
KCNQ2 Potassium Channel
M current
ion channel
biology.protein
Biophysics
M-current
Kv7 potassium channel
030217 neurology & neurosurgery
Ion channel
calcium regulation
Subjects
Details
- Language :
- English
- ISSN :
- 10916490 and 00278424
- Volume :
- 115
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....518709e26dc9e0e7ba00ad280c7a4af6