Electrostatic interactions of S4 voltage sensor in shaker K+ channel

Papazian, Diane M.; Shao, Xuesi M.; Seoh, Sang-Ah; Mock, Allan F.; Huang, Yü; Wainstock, Daniel H.

doi:10.1016/0896-6273(95)90276-7

Cited by 355 publications

(438 citation statements)

References 50 publications

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“…The eag constraint was not included, however. Two possible packing arrangements of S2, S3, and S4 were obtained that are consistent with second-site suppressor results in Shaker, suggesting that E283 in S2 interacts with R368 and R371 in S4, and K374 in S4 interacts with E293 in S2 and D316 in S3 (22,23,30). Identification of the ion-binding site in eag provides an additional structural constraint between S2 and S3 (6), and strong experimental justification now has been provided for use of Shaker and eag constraints in the same model.…”

Section: Model For Structural Rearrangements Underlying Two Stages Ofsupporting

confidence: 61%

“…Evidence for conservation of key molecular details in the mechanism of voltage-dependent activation in eag and Shaker, two divergent members of the K ϩ channel superfamily, confirms that their voltage sensors share a common structure. Although a detailed atomic structure of a voltage-gated K ϩ channel is not yet available, data from second-site suppressor analysis of Shaker and identification of the ion-binding site in eag put specific constraints on the structural organization of the voltage sensor (6,22,23,30). We previously suggested that these constraints uniquely specify the packing of S2, S3, and S4 in the voltage sensor (6).…”

Section: Model For Structural Rearrangements Underlying Two Stages Ofmentioning

confidence: 99%

See 1 more Smart Citation

Structural basis of two-stage voltage-dependent activation in K⁺channels

Silverman

Roux

Papazian

2003

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

119

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The structure of the voltage sensor and the detailed physical basis of voltage-dependent activation in ion channels have not been determined. We now have identified conserved molecular rearrangements underlying two major voltage-dependent conformational changes during activation of divergent K ؉ channels, ether-à -go-go (eag) and Shaker. Two conserved arginines of the S4 voltage sensor move sequentially into an extracellular gating pocket, where they interact with an acidic residue in S2. In eag, these transitions are modulated by a divalent ion that binds in the gating pocket. Conservation of key molecular details in the activation mechanism confirms that voltage sensors in divergent K ؉ channels share a common structure. Molecular modeling reveals that structural constraints derived from eag and Shaker specify the unique packing arrangement of transmembrane segments S2, S3, and S4 within the voltage sensor.

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Section: Model For Structural Rearrangements Underlying Two Stages Ofsupporting

confidence: 61%

Section: Model For Structural Rearrangements Underlying Two Stages Ofmentioning

confidence: 99%

Structural basis of two-stage voltage-dependent activation in K⁺channels

Silverman

Roux

Papazian

2003

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

119

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“…Our results do not preclude crucial side chain interactions between a small subset of residues in the paddle and other parts of the voltage sensor. The charge carrying Arg residues, for example, are thought to interact with acidic residues in S2 and S3 28,45 , and there appears to be specificity in the positions in S4 where charged moieties contribute to the total gating charge 17 . The Arg residues are the most conserved positions in our paddle constructs, so important interactions involving these residues are fully compatible with our results.…”

Section: Discussionmentioning

confidence: 99%

Portability of paddle motif function and pharmacology in voltage sensors

Alabi

Bahamonde

Jung

et al. 2007

Nature

205

278

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Voltage-sensing domains enable membrane proteins to sense and react to changes in membrane voltage. Although identifiable S1-S4 voltage-sensing domains are found in an array of conventional ion channels and in other membrane proteins that lack pore domains, the extent to which their voltage sensing mechanisms are conserved is unknown. Here we show that the voltage-sensor paddle, a motif composed of S3b and S4 helices, can drive channel opening with membrane depolarization when transplanted from an archaebacterial voltage-activated potassium (Kv) channel (KvAP) or voltagesensing domain proteins (Hv1 and Ci-VSP) into eukaryotic Kv channels. Tarantula toxins that partition into membranes can interact with these paddle motifs at the protein-lipid interface and similarly perturb voltage sensor activation in both ion channels and voltage-sensing domain proteins. Our results show that paddle motifs are modular, that their functions are conserved in voltage sensors, and that they move in the relatively unconstrained environment of the lipid membrane. The widespread targeting of voltage-sensor paddles by toxins demonstrates that this modular structural motif is an important pharmacological target.Ion channels that open and close in response to changes in membrane voltage have a modular architecture, with a central pore domain that determines ion selectivity, and four surrounding voltage sensing domains that move in response to changes in membrane voltage to drive opening of the pore 1-5 (Fig 1a). Although X-ray structures have now been solved for two voltage-activated potassium (Kv) channels 1, 6-9 , the structural basis of voltage sensing remains controversial 10-12 . A seminal observation in the X-ray structures of the KvAP channel, an archaebacterial Kv channel from Aeropyrum pernix, was that the S3b helix and the charge-bearing S4 helix within the voltage-sensing domain form a helix-turn-helix structure, termed the paddle motif 1, 8, 9 . Studies on KvAP 1, 9, 13-16 suggest that this voltage-sensor paddle is buried in the membrane and that it moves at the protein-lipid interface, which contrasts with models for eukaryotic Kv channels where the S4 helix is protected from membrane lipids by other regions of the protein 10-12, 17-21 . Voltage-sensing domains have also recently been described in voltage-sensing proteins that lack associated pore domains 5, 22, 23 . In Ci-VSP the voltage-sensing domain is coupled to a phosphatase domain and in Hv1 the voltage-sensing domain itself is thought to function as a proton channel. Here we explore whether the mechanisms of voltage-sensing are conserved between the distantly related eukaryotic and Chimeras between Kv channelsWe began by generating chimeras between the archaebacterial KvAP channel 24 and the eukaryotic Kv2.1 channel from rat brain 25 to define the interchangeable regions. Transfer of the KvAP pore domain into Kv2.1 results in channels that open in response to membrane depolarization (Fig 1a ; Supplementary Fig 1 and Table 1), so long as the S4-S5 linker hel...

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“…While many factors are important for normal protein structure, the fact that the L1433K/E mutations affect inactivation similarly excludes the possibility that L1433R alters channel packing by forming additional salt bridges with adjacent acidic amino acids. This also excludes the possibility that addition of a charge to residue 1433 directly involves the electrostatic network inside the protein, which is thought to be important in maintaining the structure of Shaker potassium channels (Papazian et al, 1995). A possible mechanism by which L1433K/E mutations affect inactivation is the disruption ofa hydrophobic interaction with residues of D4/$4.…”

Section: L1433r and R1448c Mutations Affect Hskm1 Inactivation Differmentioning

confidence: 99%

Paramyotonia congenita mutations reveal different roles for segments S3 and S4 of domain D4 in hSkM1 sodium channel gating.

George

Horn

et al. 1996

The Journal of General Physiology

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Mutations in the gene encoding the voltage-gated sodium channel of skeletal muscle (SkM1) have been identified in a group of autosomal dominant diseases, characterized by abnormalities of the sarcolemmal excitability, that include paramyotonia congenita (PC) and hyperkalemic periodic paralysis (HYPP). We previously reported that PC mutations cause in common a slowing of inactivation in the human SkM1 sodium channel. In this investigation, we examined the molecular mechanisms responsible for the effects of L1433R, located in D4/$3, on channel gating by creating a series of additional mutations at the 1433 site. Unlike the R1448C mutation, found in D4/$4, which produces its effects largely due to the loss of the positive charge, change of the hydropathy of the side chain rather than charge is the primary factor mediating the effects of L1433R. These two mutations also differ in their effects on recovery from inactivation, conditioned inactivation, and steady state inactivation of the hSkM1 channels. We constructed a double mutation containing both L1433R and R1448C. The double mutation closely resembled R1448C with respect to alterations in the kinetics of inactivation during depolarization and voltage dependence, but was indistinguishable from L1433R in the kinetics of recovery from inactivation and steady state inactivation. No additive effects were seen, suggesting that these two segments interact during gating. In addition, we found that these mutations have different effects on the delay of recovery from inactivation and the kinetics of the tail currents, raising a question whether this delay is a reflection of the deactivation process. These results suggest that the $3 and $4 segments play distinct roles in different processes of hSkM1 channel gating: D4/$4 is critical for the deactivation and inactivation of the open channel while D4/$3 has a dominant role in the recovery of inactivated channels. However, these two segments interact during the entry to, and exit from, inactivation states.

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Electrostatic interactions of S4 voltage sensor in shaker K+ channel

Cited by 355 publications

References 50 publications

Structural basis of two-stage voltage-dependent activation in K⁺channels

Structural basis of two-stage voltage-dependent activation in K⁺channels

Portability of paddle motif function and pharmacology in voltage sensors

Paramyotonia congenita mutations reveal different roles for segments S3 and S4 of domain D4 in hSkM1 sodium channel gating.

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Electrostatic interactions of S4 voltage sensor in shaker K+ channel

Cited by 355 publications

References 50 publications

Structural basis of two-stage voltage-dependent activation in K+channels

Structural basis of two-stage voltage-dependent activation in K+channels

Portability of paddle motif function and pharmacology in voltage sensors

Paramyotonia congenita mutations reveal different roles for segments S3 and S4 of domain D4 in hSkM1 sodium channel gating.

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Structural basis of two-stage voltage-dependent activation in K⁺channels

Structural basis of two-stage voltage-dependent activation in K⁺channels