K channel gating by an affinity-switching selectivity filter

VanDongen, Antonius M.J.

doi:10.1073/pnas.0308743101

Cited by 45 publications

(56 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A stochastic model of the selectivity filter can be conceived in which the channel alternates between a cation-bound conformation (to hold ions) and a cation-free, conducting conformation (to release ions). This model is conceptually consistent with a previously proposed mechanism for ion selection and gating of the filter 31 , in which the channel alternates between an ion-selective, cation-bound, nonconducting conformation and a cation-free, conducting conformation. This model is sufficient to explain both ion selection and gating 13 and is now supported by direct experimental evidence.…”

Section: Kcsa Channel Conductancesupporting

confidence: 73%

Conformational dynamics of the KcsA potassium channel governs gating properties

Baker

Tzitzilonis

Kwiatkowski

et al. 2007

Nat Struct Mol Biol

123

136

View full text Add to dashboard Cite

K + channels conduct and regulate K + flux across the cell membrane. Several crystal structures and biophysical studies of tetrameric ion channels have revealed many of the structural details of ion selectivity and gating. A narrow pore lined with four arrays of carbonyl groups is responsible for ion selectivity, whereas a conformational change of the four inner transmembrane helices (TM2) is involved in gating. We used NMR to examine full-length KcsA, a prototypical K + channel, in its open, closed and intermediate states. These studies reveal that at least two conformational states exist both in the selectivity filter and near the C-terminal ends of the TM2 helices. In the ion-conducting open state, we observed rapid structural exchange between two conformations of the filter, presumably of low and high K + affinity, respectively. Such measurements of millisecond-timescale dynamics reveal the basis for simultaneous ion selection and gating.The simplest structural definition of ion channel gating is the ability to alternate, in a signaldependent way, between states that selectively permit the flow of ions (open) or do not (closed). In the closed state, generally a default state, K + channels inhibit ion flow with high efficacy. In the open state, two opposing tasks must be carried out near the diffusion limit: ion selection and permeation 1 . Energetically, ion selection requires spatial coordination that favors K + over other cations, whereas permeation requires the rapid release of the cation from these recognition sites. This 'hold-and-release' feature underlies the unique structural and dynamical properties of the channel.Crystal structures of K + channels of prokaryotic origin (KcsA 2 , MthK 3 , KirBac1.1 (ref. 4), KvAP 5 and NaK 6 ) have revealed a universal structural framework for these tasks. To explain ion selectivity, the structures show a narrow filter composed of four successive layers of main chain carbonyl oxygen atoms, which act as surrogate waters for the dehydrated K + ions (1.35-Å radius) as they pass through the filter. This unique spatial geometry results from the signature filter amino acid sequence, Gly-Tyr-Gly, in which the two glycines enable positive φ/ψ angles of the protein backbone so that the K + -coordinating carbonyl oxygens can all point inward to the pore axis simultaneously 7 to perform ion selection 8,9 . For gating of the channel, the pore-lining C-terminal ends of the inner AUTHOR CONTRIBUTIONSK.A.B. and C.T. prepared KcsA; K.A.B., C.T., W.K. and R.R. collected and analyzed NMR data; K.A.B., C.T., S.C. and R.R. contributed to scientific discussions and prepared the manuscript. Fig. 3 online), we have obtained B85% of the sequential backbone assignments of full-length KcsA(tox) at pH 7 (Fig. 1). A residue-specific secondary structure analysis based on positive 13 Cα chemical shift deviations from a random coil (Fig. 1a), amide-H 2 O exchange ( Supplementary Fig. 4b online) and protein-detergent NOEs ( Supplementary Fig. 4a) revealed the presence of the following he...

show abstract

Section: Kcsa Channel Conductancesupporting

confidence: 73%

Conformational dynamics of the KcsA potassium channel governs gating properties

Baker

Tzitzilonis

Kwiatkowski

et al. 2007

Nat Struct Mol Biol

123

136

View full text Add to dashboard Cite

show abstract

“…This concertedassociation/dissociation hypothesis allowed for the possibility that permeation might proceed according to just two steps. 5 This two-step hypothesis is now supported by a large group of simulations, [6][7][8][9][10][11][12][13][14][15] but no comparison of this two-step model with experiment has yet been conducted.…”

Section: Introductionmentioning

confidence: 76%

“…5) is also supported by a large group of MD simulations. [6][7][8][9][10][11][12][13][14][15] Despite this extensive prior support, Fig. 6 shows the first published fit of this minimal saturating model to any experimental data.…”

Section: A Symmetric A/d Modelmentioning

confidence: 99%

See 1 more Smart Citation

A permeation theory for single-file ion channels: One- and two-step models

Nelson

2011

The Journal of Chemical Physics

View full text Add to dashboard Cite

How many steps are required to model permeation through ion channels? This question is investigated by comparing one-and two-step models of permeation with experiment and MD simulation for the first time. In recent MD simulations, the observed permeation mechanism was identified as resembling a Hodgkin and Keynes knock-on mechanism with one voltage-dependent rate-determining step [Jensen et al., PNAS 107, 5833 (2010)]. These previously published simulation data are fitted to a one-step knock-on model that successfully explains the highly non-Ohmic current-voltage curve observed in the simulation. However, these predictions (and the simulations upon which they are based) are not representative of real channel behavior, which is typically Ohmic at low voltages. A two-step association/dissociation (A/D) model is then compared with experiment for the first time. This two-parameter model is shown to be remarkably consistent with previously published permeation experiments through the MaxiK potassium channel over a wide range of concentrations and positive voltages. The A/D model also provides a first-order explanation of permeation through the Shaker potassium channel, but it does not explain the asymmetry observed experimentally. To address this, a new asymmetric variant of the A/D model is developed using the present theoretical framework. It includes a third parameter that represents the value of the "permeation coordinate" (fractional electric potential energy) corresponding to the triply occupied state n of the channel. This asymmetric A/D model is fitted to published permeation data through the Shaker potassium channel at physiological concentrations, and it successfully predicts qualitative changes in the negative current-voltage data (including a transition to super-Ohmic behavior) based solely on a fit to positive-voltage data (that appear linear). The A/D model appears to be qualitatively consistent with a large group of published MD simulations, but no quantitative comparison has yet been made. The A/D model makes a network of predictions for how the elementary steps and the channel occupancy vary with both concentration and voltage. In addition, the proposed theoretical framework suggests a new way of plotting the energetics of the simulated system using a one-dimensional permeation coordinate that uses electric potential energy as a metric for the net fractional progress through the permeation mechanism. This approach has the potential to provide a quantitative connection between atomistic simulations and permeation experiments for the first time.

show abstract

“…We mention two examples: (i) the playground is a cell, the individuals are potassium ions, the door is a potassium channel (Hille, 2001;VanDongen, 2004), and the problem is that of computing the ionic current through the channel (Andreucci et al, 2011;. This is a very important question in biology, indeed ionic channel are present in almost all living beings and play a key role in regulating the ionic concentration inside the cells.…”

Section: Introductionmentioning

confidence: 99%

Flux through a Time-periodic Gate - Monte Carlo Test of a Homogenization Result

Andreucci¹,

Bellaveglia²,

Cirillo³

et al. 2013

Proceedings of the 3rd International Conference on Simulation and Modeling Methodologies, Technologies and Applications

View full text Add to dashboard Cite

Abstract:We investigate via Monte Carlo numerical simulations and theoretical considerations the outflux of random walkers moving in an interval bounded by an interface exhibiting channels (pores, doors) which undergo an open/close cycle according to a periodic schedule. We examine the onset of a limiting boundary behavior characterized by a constant ratio between the outflux and the local density, in the thermodynamic limit. We compare such a limit with the predictions of a theoretical model already obtained in the literature as the homogenization limit of a suitable diffusion problem.

show abstract

K channel gating by an affinity-switching selectivity filter

Cited by 45 publications

References 30 publications

Conformational dynamics of the KcsA potassium channel governs gating properties

Conformational dynamics of the KcsA potassium channel governs gating properties

A permeation theory for single-file ion channels: One- and two-step models

Flux through a Time-periodic Gate - Monte Carlo Test of a Homogenization Result

Contact Info

Product

Resources

About