Article

Voltage sensor conformations in the open and closed states in ROSETTA structural models of K+ channel

Department of Biochemistry , University of Washington Seattle, Seattle, Washington, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 06/2006; 103(19):7292-7. DOI: 10.1073/pnas.0602350103
Source: PubMed

ABSTRACT Voltage-gated ion channels control generation and propagation of action potentials in excitable cells. Significant progress has been made in understanding structure and function of the voltage-gated ion channels, highlighted by the high-resolution open-state structure of the voltage-gated potassium channel, K(v)1.2. However, because the structure of the closed state is unknown, the gating mechanism remains controversial. We adapted the rosetta membrane method to model the structures of the K(v)1.2 and KvAP channels using homology, de novo, and domain assembly methods and selected the most plausible models using a limited number of experimental constraints. Our model of K(v)1.2 in the open state is very similar in overall topology to the x-ray structure of this channel. Modeling of KvAP in the open state suggests that orientation of the voltage-sensing domain relative to the pore-forming domain is considerably different from the orientation in the K(v)1.2 open state and that the magnitude of the vertical movement of S4 is significantly greater. Structural modeling of closed state of K(v)1.2 suggests gating movement that can be viewed as a sum of two previously suggested mechanisms: translation (2-4 A) plus rotation ( approximately 180 degrees ) of the S4 segment as proposed in the original "sliding helix" or "helical screw" models coupled with a rolling motion of the S1-S3 segments around S4, similar to recent "transporter" models of gating. We propose a unified mechanism of voltage-dependent gating for K(v)1.2 and KvAP in which this major conformational change moves the gating charge across the electric field in an analogous way for both channels.

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Available from: Vladimir Yarov-Yarovoy, Feb 24, 2015
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    • "Although there is no available atomic-resolution structure of a Kv channel in the resting state, the first four arginines (R1-R4) of Kv1.2 are generally thought to stay in a 'down' position in the resting state compared with the open state46,47. A recent long-time all-atom MD simulation also supports the downward movement of arginines5. "
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    ABSTRACT: Voltage-gated potassium (Kv) channels derive their voltage sensitivity from movement of gating charges in voltage-sensor domains (VSDs). The gating charges translocate through a physical pathway in the VSD to open or close the channel. Previous studies showed that the gating charge pathways of Shaker and Kv1.2-2.1 chimeric channels are occluded, forming the structural basis for the focused electric field and gating charge transfer center. Here, we show that the gating charge pathway of the voltage-gated KCNQ2 potassium channel, activity reduction of which causes epilepsy, can accommodate various small molecule ligands. Combining mutagenesis, molecular simulation and electrophysiological recording, a binding model for the probe activator, ztz240, in the gating charge pathway was defined. This information was used to establish a docking-based virtual screening assay targeting the defined ligand-binding pocket. Nine activators with five new chemotypes were identified, and in vivo experiments showed that three ligands binding to the gating charge pathway exhibit significant anti-epilepsy activity. Identification of various novel activators by virtual screening targeting the pocket supports the presence of a ligand-binding site in the gating charge pathway. The capability of the gating charge pathway to accommodate small molecule ligands offers new insights into the gating charge pathway of the therapeutically relevant KCNQ2 channel.Cell Research advance online publication 25 June 2013; doi:10.1038/cr.2013.82.
    Cell Research 06/2013; 23(9). DOI:10.1038/cr.2013.82 · 11.98 Impact Factor
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    • "Starting from the sliding helix (Larsson et al., 1996; Yang et al., 1996) or helical screw model (Guy and Seetharamulu, 1986; Ahern and Horn, 2005), the transporter model (Starace and Bezanilla, 2001, 2004; Chanda et al., 2005), and the paddle model (Jiang et al., 2003; Ruta et al., 2005), the current understanding converges more and more toward a single consensus model for the gating movement of the voltage sensor (Khalili-Araghi et al., 2010; Vargas et al., 2011; Jensen et al., 2012; Yarov-Yarovoy et al., 2012). According to this consensus, the positive gating charges on the S4 are stabilized by pairwise interactions with anionic charges in S1–S3 aligned along the interface to S4 (Papazian et al., 1995; Tiwari-Woodruff et al., 2000; Yarov-Yarovoy et al., 2006). During activation, the positive charges “jump” from one negative charge to the following one leading to the conformational change of the voltage sensor. "
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    ABSTRACT: Voltage-gated ion channels play a central role in the generation of action potentials in the nervous system. They are selective for one type of ion - sodium, calcium, or potassium. Voltage-gated ion channels are composed of a central pore that allows ions to pass through the membrane and four peripheral voltage sensing domains that respond to changes in the membrane potential. Upon depolarization, voltage sensors in voltage-gated potassium channels (Kv) undergo conformational changes driven by positive charges in the S4 segment and aided by pairwise electrostatic interactions with the surrounding voltage sensor. Structure-function relations of Kv channels have been investigated in detail, and the resulting models on the movement of the voltage sensors now converge to a consensus; the S4 segment undergoes a combined movement of rotation, tilt, and vertical displacement in order to bring 3-4e(+) each through the electric field focused in this region. Nevertheless, the mechanism by which the voltage sensor movement leads to pore opening, the electromechanical coupling, is still not fully understood. Thus, recently, electromechanical coupling in different Kv channels has been investigated with a multitude of techniques including electrophysiology, 3D crystal structures, fluorescence spectroscopy, and molecular dynamics simulations. Evidently, the S4-S5 linker, the covalent link between the voltage sensor and pore, plays a crucial role. The linker transfers the energy from the voltage sensor movement to the pore domain via an interaction with the S6 C-termini, which are pulled open during gating. In addition, other contact regions have been proposed. This review aims to provide (i) an in-depth comparison of the molecular mechanisms of electromechanical coupling in different Kv channels; (ii) insight as to how the voltage sensor and pore domain influence one another; and (iii) theoretical predictions on the movement of the cytosolic face of the Kv channels during gating.
    Frontiers in Pharmacology 09/2012; 3:166. DOI:10.3389/fphar.2012.00166 · 3.80 Impact Factor
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    • "It is likely that interaction between S4–S5 linker and distal S6 takes place also at the closed state of the channel. Molecular dynamic simulations studies predict the movement pattern of S4–S5 linker as well as its interaction with S6 during the voltage gating process of Shaker-related channels (Yarov-Yarovoy et al., 2006; Jensen et al., 2012). Summarizing experimental and theoretical studies Blunck and Batulan discuss two alternative scenarios where S4–S5 linker functions (1) as a spring and (2) as a bolt (see current review issue). "
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    ABSTRACT: The activation of voltage-dependent ion channels is initiated by potential-induced conformational rearrangements in the voltage-sensor domains that propagates to the pore domain (PD) and finally opens the ion conduction pathway. In potassium channels voltage-sensors are covalently linked to the pore via S4-S5 linkers at the cytoplasmic site of the PD. Transformation of membrane electric energy into the mechanical work required for the opening or closing of the channel pore is achieved through an electromechanical coupling mechanism, which involves local interaction between residues in S4-S5 linker and pore-forming alpha helices. In this review we discuss present knowledge and open questions related to the electromechanical coupling mechanism in most intensively studied voltage-gated Shaker potassium channel and compare structure-functional aspects of coupling with those observed in distantly related ion channels. We focus particularly on the role of electromechanical coupling in modulation of the constitutive conductance of ion channels.
    Frontiers in Pharmacology 07/2012; 3:145. DOI:10.3389/fphar.2012.00145 · 3.80 Impact Factor
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