Coupling between the voltage-sensing and pore domains in a voltage-gated potassium channel

Schow, Eric V.; Freites, J. Alfredo; Nizkorodov, Alex; White, Stephen H.; Tobias, Douglas J.

doi:10.1016/j.bbamem.2012.02.029

Cited by 19 publications

(23 citation statements)

References 74 publications

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“…Although one site is clearly not enough to draw general conclusions on the mechanisms of voltage sensor movement, we can make a few tentative comparisons with previous results and simulations. The present results agree with the limited vertical movements reported before (Cha et al, 1999; Posson et al, 2005; Posson and Selvin, 2008) and with the possibility of tangential movement of the VSD as reported by (Posson and Selvin, 2008; Schow et al, 2012) and also observed in long MD simulations by (Jensen et al, 2012). On the other hand, the present results do not agree with a very large vertical translation of the S4 segment (Tao et al, 2010; Henrion et al, 2012; Jensen et al, 2012).…”

Section: Discussionsupporting

confidence: 94%

Nano-Positioning System for Structural Analysis of Functional Homomeric Proteins in Multiple Conformations

et al. 2012

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SUMMARY Proteins may undergo multiple conformational changes required for their function. One strategy used to estimate target site positions in unknown structural conformations involves single-pair resonance energy transfer (RET) distance measurements. However, interpretation of inter-residue distances is difficult when applied to three-dimensional structural rearrangements, especially in homomeric systems. We developed a novel method using inverse trilateration/triangulation to map target sites within a homomeric protein in all defined states with simultaneous functional recordings. The procedure accounts for probe diffusion to accurately determine the three-dimensional position and confidence region of lanthanide LRET donors attached to a target site (one/subunit), relative to a single fluorescent acceptor placed in a static site. As a first application, the method is used to determine the position of a functional voltage-gated potassium channel’s voltage sensor. Our results verify the crystal structure relaxed conformation and report on the resting and active conformations for which crystal structures are not available.

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Section: Discussionsupporting

confidence: 94%

Nano-Positioning System for Structural Analysis of Functional Homomeric Proteins in Multiple Conformations

et al. 2012

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“…These family members share six TM and are gated by voltage. The VSD-PD assembly represents an exquisite molecular electromechanical coupling device, which converts potential energy of the membrane electric field into the mechanical work needed to control the selective permeation of potassium ions (55). The pore domain (PD) represents a tetramer of two membrane-spanning a helixes that are connected with each other via a P-loop, which is responsible for potassium ion selectivity.…”

Section: Structure Of Potassium Channelsmentioning

confidence: 99%

“…Voltage-sensing domains are connected to the PD by a linker, known as S4-S5 linker at the cytoplasmic side of the membrane. The VSD-PD assembly represents an exquisite molecular electromechanical coupling device, which converts potential energy of the membrane electric field into the mechanical work needed to control the selective permeation of potassium ions (55).…”

Section: Voltage-gated Six Transmembrane Potassium Channelsmentioning

confidence: 99%

Potassium Channels: Structures, Diseases, and Modulators

Tian

Zhu

et al. 2013

Chem Biol Drug Des

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Potassium channels participate in many critical biological functions and play important roles in a variety of diseases. In recent years, many significant discoveries have been made which motivate us to review these achievements. The focus of our review is mainly on three aspects. Firstly, we try to summarize the latest developments in structure determinants and regulation mechanism of all types of potassium channels. Secondly, we review some diseases induced by or related to these channels. Thirdly, both qualitative and quantitative approaches are utilized to analyze structural features of modulators of potassium channels. Our analyses further prove that modulators possess some certain natural-product scaffolds. And pharmacokinetic parameters are important properties for organic molecules. Besides, with in silico methods, some features that can be used to differentiate modulators are derived. There is no doubt that all these studies on potassium channels as possible pharmaceutical targets will facilitate future translational research. All the strategies developed in this review could be extended to studies on other ion channels and proteins as well.

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“…Although it is very difficult to show rigorously that the rms constraint will accurately reproduce transition pathways for large conformational changes, within the context of VSD simulations it has been shown to reproduce results from long and unbiased simulations. Most notably Schow et al (31) reported TMD application for studies of the gating of the bacterial voltage-gated potassium channel KvAP. TMD simulations propagating the VSD gating provided an impressive qualitative agreement with Jensen et al (32) who ran unconstrained simulations on the channel under hyperpolarized conditions and observed a similar gating transition.…”

Section: Thermodynamic Mutant Cycle Analysis Suggests Charge-chargementioning

confidence: 99%

Hydrophobic plug functions as a gate in voltage-gated proton channels

Chamberlin

Qiu

Rebolledo

et al. 2013

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

150

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Voltage-gated proton (Hv1) channels play important roles in the respiratory burst, in pH regulation, in spermatozoa, in apoptosis, and in cancer metastasis. Unlike other voltage-gated cation channels, the Hv1 channel lacks a centrally located pore formed by the assembly of subunits. Instead, the proton permeation pathway in the Hv1 channel is within the voltage-sensing domain of each subunit. The gating mechanism of this pathway is still unclear. Mutagenic and fluorescence studies suggest that the fourth transmembrane (TM) segment (S4) functions as a voltage sensor and that there is an outward movement of S4 during channel activation. Using thermodynamic mutant cycle analysis, we find that the conserved positively charged residues in S4 are stabilized by countercharges in the other TM segments both in the closed and open states. We constructed models of both the closed and open states of Hv1 channels that are consistent with the mutant cycle analysis. These structural models suggest that electrostatic interactions between TM segments in the closed state pull hydrophobic residues together to form a hydrophobic plug in the center of the voltage-sensing domain. Outward S4 movement during channel activation induces conformational changes that remove this hydrophobic plug and instead insert protonatable residues in the center of the channel that, together with water molecules, can form a hydrogen bond chain across the channel for proton permeation. This suggests that salt bridge networks and the hydrophobic plug function as the gate in Hv1 channels and that outward movement of S4 leads to the opening of this gate.voltage gating | mutagenesis cycle | molecular dynamics | VSOP | blocker T he best-studied function of voltage-gated proton (Hv1) channels is in the immune system, where the activity of Hv1 channels has been shown to play a key role in charge compensation for the electron extrusion by NADPH oxidase during the respiratory burst in phagocytes (1, 2). In addition, this channel is also found in many other cell types including neurons, sperm, and lung airway epithelia cells, where it has been implicated in acid extrusion, male fertility, and the pathology of asthma, respectively (3, 4). During stroke, the activity of Hv1 channels exacerbates neuronal death (5). In 2006, two independent groups identified the genes coding for the Hv1 channel in humans (hHv1) (6) and mice and Ciona intestinalis (voltage-sensing only protein; we call it "Ci-Hv1" in this paper) (7). The sequences of Hv1/(VSOP) are homologous to the sequences of the voltagesensing domain (VSD) of other voltage-gated ion channels, such as voltage-gated sodium, potassium, and calcium channels (Nav, Kv, and Cav channels), and the voltage sensor-containing phosphatase VSP (6, 7). Hydropathy analysis of the Hv1 sequence suggests the existence of four transmembrane (TM) segments (Fig. 1A), designated S1 to S4, similar to the four TM segments of the VSD of Kv channels (Fig. S1). However, Hv1 channels lack the last two TM segments of Kv channels that make up t...

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Coupling between the voltage-sensing and pore domains in a voltage-gated potassium channel

Cited by 19 publications

References 74 publications

Nano-Positioning System for Structural Analysis of Functional Homomeric Proteins in Multiple Conformations

Nano-Positioning System for Structural Analysis of Functional Homomeric Proteins in Multiple Conformations

Potassium Channels: Structures, Diseases, and Modulators

Hydrophobic plug functions as a gate in voltage-gated proton channels

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