Molecular mechanism of voltage sensor movements in a potassium channel

Elliott, David; Neale, Edward J.; Aziz, Qadeer; Dunham, James P.; Munsey, Tim S.; Hunter, Malcolm; Sivaprasadarao, Asipu

doi:10.1038/sj.emboj.7600484

Cited by 34 publications

(34 citation statements)

References 49 publications

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“…Amino acid side chains are represented approximately in the ROSETTA membrane method, and hence the accuracy of the models is limited to 2-4 Å at best (45). Among the 10 largest clusters of models (see Methods), the third cluster agreed with experimental data demonstrating proximity of residues at the extracellular ends of S4 from one subunit and S5 from the adjacent subunit (32,(35)(36)(37) (Fig. 2 A and B).…”

Section: Resultssupporting

confidence: 72%

“…S4 in our closed-state model of K v 1.2 is in close proximity to S5 from the adjacent subunit (Fig. 3 A and B), in agreement with results suggesting this topological arrangement in the closed state (35)(36)(37)49). These segments packed significantly more tightly in our closed-state model compared with the open-state structure, which is realistic because the hydrophobic face of the S4 helix rotated Ϸ180°from the lipid environment in the open state to the protein environment at the S4-S5 interface in the closed state (Fig.…”

Section: Model Of Kv12 In the Closedsupporting

confidence: 79%

“…In contrast to all of these findings, a ''paddle'' model of gating suggested by the x-ray structure of KvAP proposed that the S4 moves 15-20 Å through the lipid bilayer during the gating process (30, 31). A major goal of our structural modeling work is to develop a gating model that reconciles these seemingly inconsistent views.Structural models of the voltage-gated ion channels in the closed and open states have been proposed based on multiple modeling strategies (10,27,(32)(33)(34)(35)(36)(37), including a specific gating model based on a transporter mechanism (27). Laine et al (32) proposed that the VSD of one subunit interacts with the PD of the neighboring subunit in the clockwise direction if viewed from the extracellular side of the membrane, based on a combination of chemical crosslinking and modeling, and this proposal has been confirmed by the K v 1.2 structure (9).…”

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confidence: 99%

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Voltage sensor conformations in the open and closed states in rosetta structural models of K ⁺ channels

Yarov‐Yarovoy¹,

Baker

Catterall³

2006

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

215

249

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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, Kv1.2. 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 Kv1.2 and KvAP channels using homology, de novo, and domain assembly methods and selected the most plausible models using a limited number of experimental constraints. suggests gating movement that can be viewed as a sum of two previously suggested mechanisms: translation (2-4 Å) plus rotation (Ϸ180°) 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 voltagedependent gating for K v1.2 and KvAP in which this major conformational change moves the gating charge across the electric field in an analogous way for both channels.membrane protein ͉ ROSETTA method ͉ voltage-gated ion channel V oltage-gated potassium (Kv) channels are members of the voltage-gated ion channel superfamily (1, 2), which is important for initiation and propagation of action potentials in excitable cells. They are composed of four identical or homologous subunits, each containing six transmembrane segments: S1-S6. Segments S1-S4 form the voltage-sensing domain (VSD), and segments S5 and S6 connected by the P loop, which is involved in ion selectivity, comprise the pore-forming domain (PD). S4 has four gating-charge-carrying arginines (R1-R4) spaced at intervals of three amino acid residues, which are highly conserved and are thought to play a key role in coupling changes in membrane voltage to opening and closing of the pore (3-5). In the Kv channels Ϸ13 electronic charges cross the membrane electrical field per channel between the closed and open states (6-8).High-resolution structures of the bacterial potassium channel KvAP and the mammalian potassium channel K v 1.2 recently have been solved (9-11). Although the KvAP structures showed the VSD in a nonnative orientation with respect to the membrane and the PD, the K v 1.2 structure captured the VSD in a conformation that is thought to represent the open state of the channel. In addition, the structure reveals that the VSD from one subunit interacts closely with the PD of the adjacent subunit in a clockwise direction when the channel structure is viewed from the extracellular side of the membrane (9). However, the closedstate structure of these channels remains unknown, and the mechanism of action of the voltage sensor in translocating gating charge is a subject of controversy. The original ''sliding helix'' or ''helical screw'' models of gating posited that S4 moves outward along a clockwise spiral path through the protei...

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Section: Resultssupporting

confidence: 72%

Section: Model Of Kv12 In the Closedsupporting

confidence: 79%

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confidence: 99%

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Voltage sensor conformations in the open and closed states in rosetta structural models of K ⁺ channels

Yarov‐Yarovoy¹,

Baker

Catterall³

2006

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

215

249

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“…Cross-bridge formation between cysteine residues on the voltage sensor paddle and the extracellular side of S5 do not depend highly on the precise location of the cysteines (19)(20)(21)(22), and a single cysteine residue near the extracellular ''tip'' of the voltage sensor paddle can result in the formation of covalent subunit dimers, presumably through linkage of voltage sensor paddles from adjacent subunits (20). The nonspecificity of cross-bridge formation and covalent subunit dimerization mediated by single cysteine residues on the voltage sensor paddle suggests that the paddle is a highly mobile unit (Fig.…”

Section: Defining the Position Of The Kvap Voltage Sensor By Analogy mentioning

confidence: 99%

Structure of the KvAP voltage-dependent K ⁺ channel and its dependence on the lipid membrane

Lee

Chen

et al. 2005

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

293

316

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Voltage-dependent ion channels gate open in response to changes in cell membrane voltage. This form of gating permits the propagation of action potentials. We present two structures of the voltage-dependent K ؉ channel KvAP, in complex with monoclonal Fv fragments (3.9 Å) and without antibody fragments (8 Å). We also studied KvAP with disulfide cross-bridges in lipid membranes. Analyzing these data in the context of the crystal structure of Kv1.2 and EPR data on KvAP we reach the following conclusions: (i) KvAP is similar in structure to Kv1.2 with a very modest difference in the orientation of its voltage sensor; (ii) mAb fragments are not the source of non-native conformations of KvAP in crystal structures; (iii) because KvAP contains separate loosely adherent domains, a lipid membrane is required to maintain their correct relative orientations, and (iv) the model of KvAP is consistent with the proposal of voltage sensing through the movement of an argininecontaining helix-turn-helix element at the protein-lipid interface.membrane protein ͉ protein-lipid interface ͉ voltage-gated ion channel ͉ voltage sensor V oltage-dependent ion channels ''sense'' voltage differences across the cell membrane and open or close in response to its value (1). These channels contain a centrally located pore surrounded by four voltage sensors. Voltage-dependent K ϩ (Kv) channels are tetramers with four identical subunits, each with six transmembrane segments (S1-S6): S5 and S6 form the central pore at the interface between the subunits, and S1-S4 form the voltage sensors (2, 3). The voltage sensors have four to seven positively charged amino acids (usually arginine) on S4, known as gating charges, and fewer negatively charged amino acids (aspartate or glutamate) distributed on S1, S2, and S3. The voltage sensors undergo a conformational change when the pore gates open, coupling movement of the S4 gating charges within the membrane electric field to channel open probability.The first structure of a Kv channel, termed KvAP, from the archeabacterium Aeropyrum Pernix (4), was determined by crystallizing the channel as a complex with a monoclonal Fab fragment attached to its voltage sensors [Protein Data Bank (PDB) ID code 1ORQ] (5). In that structure the voltage sensors are in a non-native conformation, displaced toward the intracellular side of the transmembrane pore. Together with a second structure of the voltage sensor alone, termed the isolated voltage sensor (PDB ID code 1ORS), the following ideas about voltagedependent gating were proposed (5, 6): that the voltage sensor is a very mobile structure, presumably because it must carry charged amino acids through the membrane electric field; that the charge bearing S4 forms a helix-turn-helix with the Cterminal half of S3 (S3b), and that the helix-turn-helix moves at the protein-lipid interface a large distance. Experiments using avidin capture of biotin linked to the voltage sensor indicated that four of the S4 arginine amino acids translate 15-20 Å across the membrane. These struc...

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“…In subsequent studies based on disulfide linkage between S4 and S5 the VSD of one subunit was shown to make close contact with the pore domain of a neighbouring subunit, not with its own subunit [60,[71][72][73][74]. This proposed interaction between two neighbouring subunits was later on supported by the X-ray structure of Kv1.2 [37].…”

Section: The Vsd Connects To the Upper End Of S5 In A Neighbouring Pomentioning

confidence: 62%

Structure, Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels

Börjesson

Elinder

2008

Cell Biochem Biophys

122

146

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Voltage-gated ion channels are crucial for both neuronal and cardiac excitability. Decades of research have begun to unravel the intriguing machinery behind voltage sensitivity. Although the details regarding the arrangement and movement in the voltage-sensing domain are still debated, consensus is slowly emerging. There are three competing conceptual models: the helical-screw, the transporter, and the paddle model. In this review we explore the structure of the activated voltage-sensing domain based on the recent X-ray structure of a chimera between Kv1.2 and Kv2.1. We also present a model for the closed state. From this we conclude that upon depolarization the voltage sensor S4 moves ~13 Å outwards and rotates ~180º, thus consistent with the helical-screw model. S4 also moves relative to S3b which is not consistent with the paddle model. One interesting feature of the voltage sensor is that it partially faces the lipid bilayer and therefore can interact both with the membrane itself and with physiological and pharmacological molecules reaching the channel from the membrane.This type of channel modulation is discussed together with other mechanisms for how voltage-sensitivity is modified. Small effects on voltage-sensitivity can have profound effects on excitability. Therefore, medical drugs designed to alter the voltage dependence offer an interesting way to regulate excitability.3

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Molecular mechanism of voltage sensor movements in a potassium channel

Cited by 34 publications

References 49 publications

Voltage sensor conformations in the open and closed states in rosetta structural models of K ⁺ channels

Voltage sensor conformations in the open and closed states in rosetta structural models of K ⁺ channels

Structure of the KvAP voltage-dependent K ⁺ channel and its dependence on the lipid membrane

Structure, Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels

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Molecular mechanism of voltage sensor movements in a potassium channel

Cited by 34 publications

References 49 publications

Voltage sensor conformations in the open and closed states in rosetta structural models of K + channels

Voltage sensor conformations in the open and closed states in rosetta structural models of K + channels

Structure of the KvAP voltage-dependent K + channel and its dependence on the lipid membrane

Structure, Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels

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Voltage sensor conformations in the open and closed states in rosetta structural models of K ⁺ channels

Voltage sensor conformations in the open and closed states in rosetta structural models of K ⁺ channels

Structure of the KvAP voltage-dependent K ⁺ channel and its dependence on the lipid membrane