Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jan 7:3:100073.
doi: 10.1016/j.bbadva.2023.100073. eCollection 2023.

Modulation of the IKS channel by PIP2 requires two binding sites per monomer

Affiliations

Modulation of the IKS channel by PIP2 requires two binding sites per monomer

Audrey Deyawe Kongmeneck et al. BBA Adv. .

Abstract

The phosphatidyl-inositol-4,5-bisphosphate (PIP2) lipid has been shown to be crucial for the coupling between the voltage sensor and the pore of the potassium voltage-gated KV7 channel family, especially the KV7.1 channel. Expressed in the myocardium membrane, KV7.1 forms a complex with KCNE1 auxiliary subunits to generate the IKS current. Here we present molecular models of the transmembrane region of this complex in its three known states, namely the Resting/Closed (RC), the Intermediate/Closed (IC), and the Activated/Open (AO), robustness of which is assessed by agreement with a range of biophysical data. Molecular Dynamics (MD) simulations of these models embedded in a lipid bilayer including phosphatidyl-inositol-4,5-bisphosphate (PIP2) lipids show that in presence of KCNE1, two PIP2 lipids are necessary to stabilize each state. The simulations also show that KCNE1 interacts with both PIP2 binding sites, forming a tourniquet around the pore and preventing its opening. The present investigation provides therefore key molecular elements that govern the role of PIP2 in KCNE1 modulation of IKS channels, possibly a common mechanism by which auxiliary KCNE subunits might modulate a variety of other ion channels.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Image, graphical abstract
Graphical abstract
Fig 1
Fig. 1
IKS MD systems. Representation of IKS models in absence (left) and presence (right) of KCNE1’s (gray ribbons) PIP2 binding site, each embedded in a POPC membrane (in yellow spheres) with PIP2 lipids (in red spheres). Two KV7.1 subunits are shown for clarity. The transmembrane segments are represented in ribbons. The VSD segments are colored in cyan, S4 in blue, S4-S5LINKER in brown and PD segments in orange. The membrane-embedded models are surrounded by water (in transparent blue surface) as well as K+ (purple spheres) and Cl (green spheres) ions.
Fig 2
Fig. 2
Validation of IKS models through pore radii calculations The graphs report the average pore radii (left) along the conduction pathway of KV7.1 (black curves) IKS 8PIP2 (purple curves) and IKS 4PIP2 (beige curves) models in A. AO state B. Intermediate state and C. RC state. Averages radii at the levels of residues G345, S349 and L353 are depicted in yellow, orange and red curves, respectively. The right panels show cartoon representations of KV7.1 (black) IKS 8PIP2 (purple) and IKS 4PIP2 (beige) models. Potassium ionic (1.33 Å) and hydrodynamic radii (3.6 Å) are represented by green and blue dashed lines in the graphs, respectively. Pore solvent accessible surfaces are colored as follows. Pore radii values inferior to K+ ionic radius, are colored in red. Pore radii values ranging between K+ ionic radius and K+ hydrodynamic radius, are colored in green. Pore radii values superior to K+ hydrodynamic radius, are colored in blue.
Fig 3
Fig. 3
Conserved basic residues in the of KCNE ancillary subunits. The picture shows a sequence alignment of the transmembrane domains (TMD) of KCNE subunits, highlighted in cyan. The conserved basic residues, located at the end of the TMD, near their CTERM domains, are highlighted in blue.
Fig 4
Fig. 4
Structural mapping of KCNE1 basic residues and PIP2 lipids in the pore domain of IKS models in 8PIP2 systems Intracellular view (top panels) and side view (bottom panels) of KV7.1 pore domain segments (in orange surface) along with S4-S5LINKER (in brown ribbons), KCNE1 subunits (in gray ribbons) and PIP2 phosphate groups (in red spheres) in A. RC model, B. IO model and C. AO model. KCNE1 basic residues R67, K69 and K70 are shown in blue spheres (See Tab S4 for their detailed interactions). S4-S5LINKER residue R249 that interact with PIP2 intra in a state independent fashion is shown in blue sticks. The successive rotational movements of KCNE1 subunits predicted to occur during RC-IC and IC-AO transitions are shown in gray circled arrows. For each state, a detailed intracellular view of KCNE1 basic residues interactions (framed in black) are depicted on the right side of the side view panels.

Similar articles

References

    1. Barhanin J., Lesage F., Guillemare E., Fink M., Lazdunski M., Romey G. KvLQT1 and IsK (minK) proteins associate to form the IKS cardiac potassium current. Nature. 1996;384:78–80. - PubMed
    1. Beckstein O., Tai K., Sansom M.S.P. Not ions alone: barriers to ion permeation in nanopores and channels. J. Am. Chem. Soc. 2004;126:14694–14695. - PubMed
    1. Buck M., Bouguet-Bonnet S., Pastor R.W., MacKerell A.D. Importance of the CMAP correction to the CHARMM22 protein force field: dynamics of hen lysozyme. Biophys. J. 2006;90:L36–L38. - PMC - PubMed
    1. Careaga C.L., Falke J.J. Thermal motions of surface α-Helices in the D-Galactose chemosensory receptor. J. Mol. Biol. 1992;226:1219–1235. - PMC - PubMed
    1. Catterall W.A. Molecular properties of voltage-sensitive sodium channels. New Insights Cell Membr. Transp. Process. 1986:3–20. - PubMed

LinkOut - more resources