A Leucine Zipper Motif Essential for Gating of Hyperpolarization-activated Channels

Wemhöner, Konstantin; Silbernagel, Nicole; Marzian, Stefanie; Netter, Michael F.; Rinné, Susanne; Stansfeld, Phillip J.; Decher, Niels

doi:10.1074/jbc.m112.378513

Cited by 9 publications

(4 citation statements)

References 26 publications

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“…Our simulations reveal that pore opening involves a tradeoff between a strengthening of the S5/S6 interface at the expense of a weakening of the S6-S6 interface. This is consistent with previous mutagenesis of a leucine zipper motif between S5 and S6, which demonstrated that disruption of this motif reduces the ability of the VSD to drive pore opening ( Wemhöner et al, 2012 ). While stabilization of the S5/S6 interface upon opening is seemingly at odds with the model of Flynn and Zagotta, this difference can be reconciled by examining the mechanism of S6 gating.…”

Section: Discussionsupporting

confidence: 92%

Interplay between VSD, pore, and membrane lipids in electromechanical coupling in HCN channels

Elbahnsi

Cowgill

Burtscher

et al. 2023

eLife

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Hyperpolarized-activated and Cyclic Nucleotide-gated (HCN) channels are the only members of the voltage-gated ion channel superfamily in mammals that open upon hyperpolarization, conferring them pacemaker properties that are instrumental for rhythmic firing of cardiac and neuronal cells. Activation of their voltage-sensor domains (VSD) upon hyperpolarization occurs through a downward movement of the S4 helix bearing the gating charges, which triggers a break in the alpha-helical hydrogen bonding pattern at the level of a conserved Serine residue. Previous structural and molecular simulation studies had however failed to capture pore opening that should be triggered by VSD activation, presumably because of a low VSD/pore electromechanical coupling efficiency and the limited timescales accessible to such techniques. Here, we have used advanced modeling strategies, including enhanced sampling molecular dynamics simulations exploiting comparisons between non-domain swapped voltage-gated ion channel structures trapped in closed and open states to trigger pore gating and characterize electromechanical coupling in HCN1. We propose that the coupling mechanism involves the reorganization of the interfaces between the VSD helices, in particular S4, and the pore-forming helices S5 and S6, subtly shifting the balance between hydrophobic and hydrophilic interactions in a 'domino effect' during activation and gating in this region. Remarkably, our simulations reveal state-dependent occupancy of lipid molecules at this emergent coupling interface, suggesting a key role of lipids in hyperpolarization-dependent gating. Our model provides a rationale for previous observations and a possible mechanism for regulation of HCN channels by the lipidic components of the membrane.

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Section: Discussionsupporting

confidence: 92%

Interplay between VSD, pore, and membrane lipids in electromechanical coupling in HCN channels

Elbahnsi

Cowgill

Burtscher

et al. 2023

eLife

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“…The most recent work shows that among the structural particularity of HCN channels, a leucine-zipper motif between the S5 and S6 segments seems to be involved by stabilizing the closed state at depolarized potentials. 21 As stated above, the I f current is voltage dependent (activated by hyperpolarization; see Figure 2). An unusual property of HCN channels involves the permeability to both Na + and K + (higher permeability to K + ions than to Na + ions).…”

Section: The Hcn Channel Familymentioning

confidence: 99%

New Therapeutic Targets in Cardiology

Roubille

Tardif

2013

Circulation

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“…The open probability of the channel was not altered by L29A substitution and was similar to the wild-type. Leucine is known to interact with the hydrophobic lipid bilayer 58 and substituting it with alanine potentially alters this interaction. This disruption in lipid interaction could have possibly altered the stability of the pore region as also seen in hyperpolarization-activated cyclic nucleotide-gated channels 58 .…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of a Bacterial Homolog of Chloride Intracellular Channel (CLIC) Protein

Rao

Ponnalagu

Sukur

et al. 2017

Sci Rep

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Chloride intracellular channels (CLIC) are non-classical ion channels lacking a signal sequence for membrane targeting. In eukaryotes, they are implicated in cell volume regulation, acidification, and cell cycle. CLICs resemble the omega class of Glutathione S-transferases (GST), yet differ from them in their ability to form ion channels. They are ubiquitously found in eukaryotes but no prokaryotic homolog has been characterized. We found that indanyloxyacetic acid-94 (IAA-94), a blocker of CLICs, delays the growth of Escherichia coli. In silico analysis showed that the E. coli stringent starvation protein A (SspA) shares sequence and structural homology with CLICs. Similar to CLICs, SspA lacks a signal sequence but contains an omega GST fold. Electrophysiological analysis revealed that SspA auto-inserts into lipid bilayers and forms IAA-94-sensitive ion channels. Substituting the ubiquitously conserved residue leucine 29 to alanine in the pore-forming region increased its single-channel conductance. SspA is essential for cell survival during acid-induced stress, and we found that acidic pH increases the open probability of SspA. Further, IAA-94 delayed the growth of wild-type but not sspA null mutant E. coli. Our results for the first time show that CLIC-like proteins exist in bacteria in the form of SspA, forming functional ion channels.

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A Leucine Zipper Motif Essential for Gating of Hyperpolarization-activated Channels

Cited by 9 publications

References 26 publications

Interplay between VSD, pore, and membrane lipids in electromechanical coupling in HCN channels

Interplay between VSD, pore, and membrane lipids in electromechanical coupling in HCN channels

New Therapeutic Targets in Cardiology

Identification and Characterization of a Bacterial Homolog of Chloride Intracellular Channel (CLIC) Protein

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