Interactions Between Charged Residues in the Transmembrane Segments of the Voltage-sensing Domain in the hERG Channel

Zhang, M.; Liu, J.; Jiang, Min; Wu, Dongmei; Sonawane, Kailas D.; Guy, H. Robert; Tseng, Gea‐Ny

doi:10.1007/s00232-005-0812-1

Cited by 48 publications

(76 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This network of charge paired interactions stabilizes the S4 voltage sensor and fine tunes the voltage sensitivity of channel activation. In the S1 helix, the negatively charged residue Asp-411 has been reported to interact with the positively charged S4 helix residue Lys-438 to stabilize the closed state of the channels (29). Our findings would support this proposed interaction.…”

Section: Functional Role Of the S1 Helix In Kv111 Channelssupporting

confidence: 73%

“…This suggests that the S1 helix likely forms a complex network of intra-subunit interactions with these two helices. In Kv11.1 channels, as well as in many other Kv family members, negatively charged residues in the S1, S2, and S3 helices are thought to form charge-charge interactions with positively charged residues within the S4 helix (28,29,31,49). This network of charge paired interactions stabilizes the S4 voltage sensor and fine tunes the voltage sensitivity of channel activation.…”

Section: Functional Role Of the S1 Helix In Kv111 Channelsmentioning

confidence: 99%

See 1 more Smart Citation

The S1 helix critically regulates the finely tuned gating of Kv11.1 channels

Phan

David

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Congenital mutations in the cardiac Kv11.1 channel can cause long QT syndrome type 2 (LQTS2), a heart rhythm disorder associated with sudden cardiac death. Mutations act either by reducing protein expression at the membrane and/or by perturbing the intricate gating properties of Kv11.1 channels. A number of clinical LQTS2-associated mutations have been reported in the first transmembrane segment (S1) of Kv11.1 channels, but the role of this region of the channel is largely unexplored. In part, this is due to problems defining the extent of the S1 helix, as a consequence of its low sequence homology with other Kv family members. Here, we used NMR spectroscopy and electrophysiological characterization to show that the S1 of Kv11.1 channels extends seven helical turns, from Pro-405 to Phe-431, and is flanked by unstructured loops. Functional analysis suggests that pre-S1 loop residues His-402 and Tyr-403 play an important role in regulating the kinetics and voltage dependence of channel activation and deactivation. Multiple residues within the S1 helix also play an important role in finetuning the voltage dependence of activation, regulating slow deactivation, and modulating C-type inactivation of Kv11.1 channels. Analyses of LQTS2-associated mutations in the pre-S1 loop or S1 helix of Kv11.1 channels demonstrate perturbations to both protein expression and most gating transitions. Thus, S1 region mutations would reduce both the action potential repolarizing current passed by Kv11

show abstract

Section: Functional Role Of the S1 Helix In Kv111 Channelssupporting

confidence: 73%

Section: Functional Role Of the S1 Helix In Kv111 Channelsmentioning

confidence: 99%

The S1 helix critically regulates the finely tuned gating of Kv11.1 channels

Phan

David

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Thus, these charged amino acids are required to stabilize the fold of the S1-S4 domain such that the channel is efficiently trafficked to the plasma membrane. More recent evidence has confirmed this paradigm in both eag and hERG channels (5,10). Finally, Horrigan and co-workers (11) demonstrated a role for these salt bridges in the Ca 2ϩ -and voltage-dependent K ϩ channel, BK.…”

mentioning

confidence: 81%

“…Combinations of charge reversal mutations in S2, S3, and S4 have been shown to correct the folding of Kv channels (6,7,10), and thus we determined the effect of charge reversal mutations in KCa3.1. As shown in Fig.…”

Section: (Bottom Panel)mentioning

confidence: 99%

Role of S3 and S4 Transmembrane Domain Charged Amino Acids in Channel Biogenesis and Gating of KCa2.3 and KCa3.1

Gao

Chotoo

Balut

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

The role of positively charged arginines in the fourth transmembrane domain (S4) and a single negatively charged amino acid in the third transmembrane domain (S3) on channel biogenesis and gating of voltage-gated K ؉ channels (Kv) has been well established. Both intermediate (KCa3.1) and small (KCa2.x) conductance, Ca 2؉ -activated K ؉ channels have two conserved arginines in S4 and a single conserved glutamic acid in S3, although these channels are voltage-independent. We demonstrate that mutation of any of these charged amino acids in KCa3.1 or KCa2.3 to alanine, glutamine, or charge reversal mutations results in a rapid degradation (<30 min) of total protein, confirming the critical role of these amino acids in channel biogenesis. Mutation of the S4 arginine closest to the cytosolic side of KCa3.1 to histidine resulted in expression at the cell surface. Excised patch clamp experiments revealed that this Arg/ His mutation had a dramatically reduced open probability (P o ), relative to wild type channels. Additionally, we demonstrate, using a combination of short hairpin RNA, dominant negative, and co-immunoprecipitation studies, that both KCa3.1 and KCa2.3 are translocated out of the endoplasmic reticulum associated with Derlin-1. These misfolded channels are poly-ubiquitylated, recognized by p97, and targeted for proteasomal degradation. Our results suggest that S3 and S4 charged amino acids play an evolutionarily conserved role in the biogenesis and gating of KCa channels. Furthermore, these improperly folded K ؉ channels are translocated out of the endoplasmic reticulum in a Derlin-1-and p97-dependent fashion, poly-ubiquitylated, and targeted for proteasomal degradation.

show abstract

“…The quest to link the putative kinetic states of these phenomenological models to conformational states of the VSD started with simplified models constrained by early mutagenesis experiments (22)(23)(24) and culminated in recent years with high-resolution molecular models resulting from ingenious experiments such as double mutant experiments (25), charge reversal mutagenesis Significance Voltage-gated cation channels (VGCCs) shape cellular excitability. Their working cycle involves the complex conformational change of modular protein units called voltage sensor domains (VSDs).…”

mentioning

confidence: 99%

Free-energy landscape of ion-channel voltage-sensor–domain activation

Delemotte

Kasimova

Klein

et al. 2014

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

View full text Add to dashboard Cite

Voltage sensor domains (VSDs) are membrane-bound protein modules that confer voltage sensitivity to membrane proteins. VSDs sense changes in the transmembrane voltage and convert the electrical signal into a conformational change called activation. Activation involves a reorganization of the membrane protein charges that is detected experimentally as transient currents. These so-called gating currents have been investigated extensively within the theoretical framework of so-called discrete-state Markov models (DMMs), whereby activation is conceptualized as a series of transitions across a discrete set of states. Historically, the interpretation of DMM transition rates in terms of transition state theory has been instrumental in shaping our view of the activation process, whose free-energy profile is currently envisioned as composed of a few local minima separated by steep barriers. Here we use atomistic level modeling and well-tempered metadynamics to calculate the configurational free energy along a single transition from first principles. We show that this transition is intrinsically multidimensional and described by a rough free-energy landscape. Remarkably, a coarse-grained description of the system, based on the use of the gating charge as reaction coordinate, reveals a smooth profile with a single barrier, consistent with phenomenological models. Our results bridge the gap between microscopic and macroscopic descriptions of activation dynamics and show that choosing the gating charge as reaction coordinate masks the topological complexity of the network of microstates participating in the transition. Importantly, full characterization of the latter is a prerequisite to rationalize modulation of this process by lipids, toxins, drugs, and genetic mutations.Kv1.2 | voltage-gated ion channels | gating kinetics | electrophysiology | metadynamics V oltage sensor domains (VSDs) are key players of diverse physiological processes involving changes in transmembrane (TM) potential: electrical impulse propagation, cellular contraction, and activation of metabolic pathways are only few possible examples (1). As such, they are the target of toxins produced by many venomous animals (2) and are becoming a popular target for drug development (3). Most of what we know about VSDs comes from the study of voltage-gated cation channels, mainly potassium and sodium selective ones, each containing four distinct VSDs. VSDs are formed by a bundle of four TM helices (S1-S4) (4-7). The S4 segment contains a series of positively charged residues, called gating charges, arranged along its inward-facing side. This segment confers to VSDs their sensitivity to external voltages, by translating vertically in response to voltage changes (Fig. 1A), and determines their voltage dependency, which is tuned by the number of S4 charges and their specific interactions with their environment (8, 9).For several decades, the molecular details of the VSD activation mechanism have been investigated extensively using diverse experimental techniques such...

show abstract

Interactions Between Charged Residues in the Transmembrane Segments of the Voltage-sensing Domain in the hERG Channel

Cited by 48 publications

References 40 publications

The S1 helix critically regulates the finely tuned gating of Kv11.1 channels

The S1 helix critically regulates the finely tuned gating of Kv11.1 channels

Role of S3 and S4 Transmembrane Domain Charged Amino Acids in Channel Biogenesis and Gating of KCa2.3 and KCa3.1

Free-energy landscape of ion-channel voltage-sensor–domain activation

Contact Info

Product

Resources

About