Closed state-coupled C-type inactivation in BK channels

Yan, Jiusheng; Li, Qin; Aldrich, Richard W.

doi:10.1073/pnas.1607584113

Cited by 14 publications

(13 citation statements)

References 45 publications

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“…The same filter residues in the divalent cation-free condition with low P o at 0 mV are less organized. These structural differences may be consistent with the suggestion that the selectivity filter is the primary ion conduction gate of Slo1 (4,5). The filter distortion is also reminiscent of a C-type inactivated state of a Kv channel (28).…”

Section: Discussionsupporting

confidence: 84%

“…The exact nature of the Slo1 ion conduction gate is yet to be revealed. Subtle changes in the selectivity filter (4)(5)(6) and dewetting of the channel cavity (7) have been suggested as the possible underlying mechanisms. Unlike in canonical voltage-gated K + channels (8), four Slo1 S6 segments, each capable of rotational movements (9), remain wide apart enough even when the main gate elsewhere is closed, allowing some inhibitors to enter the channel cavity from the intracellular side (4,10).…”

mentioning

confidence: 99%

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Large-conductance Ca ²⁺ - and voltage-gated K ⁺ channels form and break interactions with membrane lipids during each gating cycle

Tian

Heinemann

Hoshi

2019

Proc. Natl. Acad. Sci. U.S.A.

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Membrane depolarization and intracellular Ca 2+ promote activation of the large-conductance Ca 2+ -and voltage-gated (Slo1) big potassium (BK) channel. We examined the physical interactions that stabilize the closed and open conformations of the ion conduction gate of the human Slo1 channel using electrophysiological and computational approaches. The results show that the closed conformation is stabilized by intersubunit ion-ion interactions involving negative residues (E321 and E324) and positive residues ( 329 RKK 331 ) at the cytoplasmic ends of the transmembrane S6 segments ("RKK ring"). When the channel gate is open, the RKK ring is broken and the positive residues instead make electrostatic interactions with nearby membrane lipid oxygen atoms. E321 and E324 are stabilized by water. When the 329 RKK 331 residues are mutated to hydrophobic amino acids, these residues form even stronger hydrophobic interactions with the lipid tails to promote the open conformation, shifting the voltage dependence of activation to the negative direction by up to 400 mV and stabilizing the selectivity filter region. Thus, the RKK segment forms electrostatic interactions with oxygen atoms from two sources, other amino acid residues (E321/E324), and membrane lipids, depending on the gate status. Each time the channel opens and closes, the aforementioned interactions are formed and broken. This lipid-dependent Slo1 gating may explain how amphipathic signaling molecules and pharmacologically active agents influence the channel activity, and a similar mechanism may be operative in other ion channels.Slo1 | BK | KCa1.1 | electrophysiology | molecular dynamics L arge-conductance Ca 2+ -and voltage-gated (Slo1) big potassium (BK) channels function generally as negative-feedback components in cellular electrical excitability by mediating K + flux in response to depolarization of transmembrane voltage (V m ) and/or an increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ). Changes in V m and binding of Ca 2+ are coupled to opening and closing of the ion conduction gate (1-3). The exact nature of the Slo1 ion conduction gate is yet to be revealed. Subtle changes in the selectivity filter (4-6) and dewetting of the channel cavity (7) have been suggested as the possible underlying mechanisms. Unlike in canonical voltage-gated K + channels (8), four Slo1 S6 segments, each capable of rotational movements (9), remain wide apart enough even when the main gate elsewhere is closed, allowing some inhibitors to enter the channel cavity from the intracellular side (4, 10).Gating of the Slo1 channel is subject to numerous regulatory influences. The channel gene undergoes extensive splicing, producing variants differing at many loci including the area immediately C terminal to S6 (11). Pore-forming Slo1 subunits coassemble with βand γ-subunits, altering multiple properties such as gating and pharmacology (12). Further, many small molecules, including H 2 S, hemin, and various fatty acids and lipids, alter Slo1 gating (13). For example, exogenous i...

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Section: Discussionsupporting

confidence: 84%

mentioning

confidence: 99%

Large-conductance Ca ²⁺ - and voltage-gated K ⁺ channels form and break interactions with membrane lipids during each gating cycle

Tian

Heinemann

Hoshi

2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Interestingly, a T-to-G mutation also induced the collapse of the SF in the closed state (27). Finally, our results provide structural snapshots that enrich the proposed four-state kinetic model for the PD of K + channels (1,8) as well as the structure of the closed and C-type inactivated states of an ion channel (28)(29)(30).…”

Section: Discussionsupporting

confidence: 71%

Inverted allosteric coupling between activation and inactivation gates in K ⁺ channels

Labro

Cortés

Tilegenova

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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The selectivity filter and the activation gate in potassium channels are functionally and structurally coupled. An allosteric coupling underlies C-type inactivation coupled to activation gating in this ion-channel family (i.e., opening of the activation gate triggers the collapse of the channel's selectivity filter). We have identified the second Threonine residue within the TTVGYGD signature sequence of K channels as a crucial residue for this allosteric communication. A Threonine to Alanine substitution at this position was studied in three representative members of the K-channel family. Interestingly, all of the mutant channels exhibited lack of C-type inactivation gating and an inversion of their allosteric coupling (i.e., closing of the activation gate collapses the channel's selectivity filter). A state-dependent crystallographic study of KcsA-T75A proves that, on activation, the selectivity filter transitions from a nonconductive and deep C-type inactivated conformation to a conductive one. Finally, we provide a crystallographic demonstration that closed-state inactivation can be achieved by the structural collapse of the channel's selectivity filter.

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“…Lipid nanodisc reconstitution was performed following the previously published methods with minor modifications (20) . On the day of nanodisc reconstitution, the Shaker Kv channel purified by Superose6 in detergent was concentrated to ~1-3 mg/ml and incubated with histidine tagged bands at a similar ratio.…”

Section: Lipid Nanodisc Reconstitution Of the Shaker Kv Channelmentioning

confidence: 99%

“…Conformational changes related to C-type inactivation also serve important roles in Ca 2+ -activated K + channels and K2P channels (20,21).…”

mentioning

confidence: 99%

Structure of the Shaker Kv channel and mechanism of slow C-type inactivation

Tan

Bae

Stix

et al. 2021

Preprint

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Voltage-activated potassium (Kv) channels open upon membrane depolarization and proceed to spontaneously inactivate. Inactivation controls neuronal firing rates and serves as a form of short-term memory, and is implicated in various human neurological disorders. Here, we use high-resolution cryo-electron microscopy and computer simulations to determine one of the molecular mechanisms underlying this physiologically crucial process. Structures of the activated Shaker Kv channel and of its W434F mutant in lipid bilayers demonstrate that C-type inactivation entails the dilation of the ion selectivity filter, and the repositioning of neighboring residues known to be functionally critical. Microsecond-scale molecular dynamics trajectories confirm these changes inhibit rapid ion permeation through the channel. This long-sought breakthrough establishes how eukaryotic K+ channels self-regulate their functional state through the plasticity of their selectivity filters.

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Closed state-coupled C-type inactivation in BK channels

Cited by 14 publications

References 45 publications

Large-conductance Ca ²⁺ - and voltage-gated K ⁺ channels form and break interactions with membrane lipids during each gating cycle

Large-conductance Ca ²⁺ - and voltage-gated K ⁺ channels form and break interactions with membrane lipids during each gating cycle

Inverted allosteric coupling between activation and inactivation gates in K ⁺ channels

Structure of the Shaker Kv channel and mechanism of slow C-type inactivation

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Closed state-coupled C-type inactivation in BK channels

Cited by 14 publications

References 45 publications

Large-conductance Ca 2+ - and voltage-gated K + channels form and break interactions with membrane lipids during each gating cycle

Large-conductance Ca 2+ - and voltage-gated K + channels form and break interactions with membrane lipids during each gating cycle

Inverted allosteric coupling between activation and inactivation gates in K + channels

Structure of the Shaker Kv channel and mechanism of slow C-type inactivation

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Product

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Large-conductance Ca ²⁺ - and voltage-gated K ⁺ channels form and break interactions with membrane lipids during each gating cycle

Large-conductance Ca ²⁺ - and voltage-gated K ⁺ channels form and break interactions with membrane lipids during each gating cycle

Inverted allosteric coupling between activation and inactivation gates in K ⁺ channels