Review
Physics, Multidisciplinary
Joao Luis Carvalho-de-Souza, Andrea Saponaro, C. A. Z. Bassetto, Oliver Rauh, Indra Schroeder, Fabio Franciolini, Luigi Catacuzzeno, Francisco Bezanilla, Gerhard Thiel, Anna Moroni
Summary: This article summarizes recent advancements in understanding the mechanisms of ion permeation and gating in channel proteins, focusing on the elementary steps of ion transport through the pore and non-canonical modes of intramolecular communication between peripheral sensory domains and the central channel pore.
ADVANCES IN PHYSICS-X
(2022)
Article
Multidisciplinary Sciences
Linus J. Conrad, Peter Proks, Stephen J. Tucker
Summary: This passage discusses a voltage-dependent gating process in the TREK-2 K+ channel, which can be modulated by small molecule agonists and high internal K+ concentrations. It is found that high ionic-strength can inhibit the channel conductance, while the activatory effect of BL1249 on channel open probability persists under these conditions. The influence of negatively charged activators like BL1249 on permeation is consistent with an electrostatic mechanism, suggesting complexity in their effect on channel gating.
Article
Multidisciplinary Sciences
Takushi Shimomura, Kiichi Hirazawa, Yoshihiro Kubo
Summary: This study reveals that different conformations of DII-S4 determine the gating modes in Two-pore channels (TPCs), with the intermediate state representing the PIP2-gating mode. TPC3 is primarily voltage-dependent, while TPC2 is PIP2-gated and nonvoltage-dependent. Furthermore, the antidepressant desipramine induces voltage dependence in TPC2, and the flavonoid naringenin biases the mode preference from PIP2-gating to desipramine-induced voltage gating.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Chemistry, Multidisciplinary
Qi Xiao, Wei-Wei Haoyang, Tao Lin, Zhan-Ting Li, Dan-Wei Zhang, Jun-Li Hou
Summary: A series of peptide-appended bisresorcinarenes were synthesized, which formed tubular conformation induced by intramolecular hydrogen bonds. These derivatives formed unimolecular artificial transmembrane channels in lipid bilayers for selective transport of monovalent cations, and showed reversible ligand-gating behavior in response to alkyl amine and Cu2+.
CHEMICAL COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Simon Scheuring
Summary: This study derives the forces and energies involved in the gating process of tetrameric cation channels using a physical model and MthK structures. It is found that the conformational change in the RCK domain of MthK opens the bundle-crossing gate through pulling via unfolded linkers. The linkers serve as entropic springs between the RCK domain and gate, storing potential energy and exerting pulling force to keep the gate open.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Yoshiaki Kise, Go Kasuya, Hiroyuki H. Okamoto, Daichi Yamanouchi, Kan Kobayashi, Tsukasa Kusakizako, Tomohiro Nishizawa, Koichi Nakajo, Osamu Nureki
Summary: Mechanisms of modulation of Kv4 channel complexes by auxiliary subunits are central to the physiological function of channels in the brain and heart. The structures of Kv4.2-KChIP1 and Kv4.2-DPP6S complexes reveal that KChIP1 prevents N-type inactivation and stabilizes the S6 conformation, while DPP6S interacts with the S1 and S2 helices to accelerate voltage-dependent movement. KChIP1 and DPP6S do not directly interact with each other in the ternary complex, suggesting two distinct modes of modulation contribute to evoke A-type currents.
Article
Biochemistry & Molecular Biology
Marco Colombini, Kevin Barnes, Kai-Ti Chang, Muhsin H. Younis, Vicente M. Aguilella
Summary: Gram-negative bacteria have a variety of channel-forming proteins in their outer membrane, some of which show voltage dependence. Triplin, a trimeric channel former, has steep voltage dependence and high inter-subunit cooperativity. Detailed molecular insights into these unusual properties have been obtained at the single-molecule level.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
David K. Jones
Summary: Cardiac hERG channels consist of hERG 1a and hERG 1b subunits, which drive cardiac action potential repolarization by regulating the movement of voltage sensor domains (VSDs). This study found that VSD relaxation delays pore closure during repolarization and that the hERG 1a PAS domain plays a role in regulating VSD movement. These findings provide the first recordings of hERG gating charge at physiological temperature and demonstrate the presence of VSD relaxation in hERG channels at physiological temperature.
SCIENTIFIC REPORTS
(2022)
Review
Physiology
Luigi Catacuzzeno, Franco Conti, Fabio Franciolini
Summary: This article reviews the retrospective on gating currents from their first recording in 1973 to the present day and their contribution to understanding channel gating. The past 50 years have witnessed great progress in elucidating the mechanisms of channel gating through the recording and analysis of gating currents. The review covers the development of the concept of gating particles and gating currents, early studies on specific channels, expansion to other channels and non-channel structures, and the translation of gating-charge/voltage-sensor movements into pore opening and associated pathologies.
JOURNAL OF GENERAL PHYSIOLOGY
(2023)
Article
Biology
Xiaoan Wu, Marta E. Perez, Sergei Yu Noskov, H. Peter Larsson
Summary: Research demonstrates that KCNE1 regulates the function of potassium channel KCNQ1 by modulating the coupling between the voltage-sensing domain and pore domain through induced rotation. This rotation leads to residue clashes that prevent the formation of a conductive intermediate state conformation of the voltage sensor.
COMMUNICATIONS BIOLOGY
(2021)
Article
Cell Biology
Qiansen Zhang, Jie Fu, Shaoying Zhang, Peipei Guo, Shijie Liu, Juwen Shen, Jiangtao Guo, Huaiyu Yang
Summary: Through molecular dynamics simulations, the study reveals the mechanism of the 'C-type' closed state in K2P channels and identifies the important role of M4 helix movements in modulating filter closing. Additionally, the study also uncovers how mutations and activators can regulate the open-closed state transitions of the channels.
JOURNAL OF MOLECULAR CELL BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Mingfeng Zhang, Yuanyue Shan, Duanqing Pei
Summary: Human Eag2 is a voltage-gated potassium channel that exhibits unique delayed rectifying gating kinetics. In this study, the authors elucidate the mechanism of how voltage opens the channel and sheds light on delayed rectifier gating. They use cryo-electron microscopy to capture multiple conformations of hEag2, revealing the dynamics of the selectivity filter and ion permeation pathway at the atomic level. The study also uncovers the involvement of the S4-S5 linker and an additional potassium ion in voltage transduction and the generation of delayed rectifier properties.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Louis Tung Faat Lai, Jayashree Balaraman, Fei Zhou, Doreen Matthies
Summary: Magnesium ions (Mg2+) are crucial for cellular physiology, and MRS2 is a channel responsible for regulating Mg2+ influx and homeostasis in mitochondria. This study provides insights into the gating residues and Mg2+ binding sites of MRS2, shedding light on the translocation and regulatory mechanisms of Mg2+.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Multidisciplinary
Lei Jin, Chang Sun, Zhongyan Li, Jie Shen, Huaqiang Zeng
Summary: By modifying compounds containing a phenylalanine moiety to form amide compounds at both ends, and adding a 15-crown-5 unit and an alkyl chain, a potassium-selective channel with a record-high K+/Na+ selectivity of 20.1 was obtained by simply adjusting the length of the alkyl chain.
CHEMICAL COMMUNICATIONS
(2023)
Article
Biology
Shuo Han, Sophia Peng, Joshua Vance, Kimberly Tran, Nhu Do, Nauy Bui, Zhenhua Gui, Shizhen Wang
Summary: This article investigates the conformational dynamics and gating mechanisms of voltage-gated proton (Hv) channels. By using single-molecule fluorescence resonance energy transfer (smFRET) with purified human voltage-gated proton (hHv1) channels reconstituted in liposomes, the real-time conformational trajectories of the S4 segment were observed. The results demonstrate that voltage and pH gradient can shift the conformational dynamics of the S4 segment, controlling the gating of the channel. The authors propose a kinetic model to explain the voltage and pH gating mechanisms in Hv channels, which may have implications for understanding the voltage sensing and gating in other voltage-gated ion channels.
Review
Chemistry, Analytical
Andreas J. W. Hartel, Siddharth Shekar, Peijie Ong, Indra Schroeder, Gerhard Thiel, Kenneth L. Shepard
ANALYTICA CHIMICA ACTA
(2019)
Article
Virology
Carter R. Murry, Irina Agarkova, Jayadri S. Ghosh, Fiona C. Fitzgerald, Roger M. Carlson, Brigitte Hertel, Kerri Kukovetz, Oliver Rauh, Gerhard Thiel, James L. Van Etten
Article
Physiology
Laura-Marie Winterstein, Kerri Kukovetz, Ulf-Peter Hansen, Indra Schroeder, James L. Van Etten, Anna Moroni, Gerhard Thiel, Oliver Rauh
Summary: The lipid composition of cell membranes affects the function of transmembrane proteins, such as ion channels. Cholesterol and anionic phospholipids can impact the unitary conductance and gating of K+ channels, with anionic phospholipids generally augmenting unitary conductance. The presence of cationic amino acids at the lipid-protein interface may explain the different sensitivity of channels to anionic phospholipids.
JOURNAL OF GENERAL PHYSIOLOGY
(2021)
Article
Cell Biology
Anja J. Engel, Marina Kithil, Markus Langhans, Oliver Rauh, Matea Cartolano, James L. Van Etten, Anna Moroni, Gerhard Thiel
Summary: The study found that biased frequency of synonymous codons can affect protein localization within cells, thus modulating protein function through different steps such as transcription, translation, and folding.
Article
Physiology
Tobias S. Gabriel, Ulf-Peter Hansen, Martin Urban, Nils Drexler, Tobias Winterstein, Oliver Rauh, Gerhard Thiel, Stefan M. Kast, Indra Schroeder
Summary: The study investigates the relationship between ions in the selectivity filter of K+ channels and the release kinetics of a blocker, revealing that K+ occupation probability is unaffected by the blocker due to ion-carbonyl attraction. The model derived from data and calculations shows that the blocker release kinetics in Kcv(NTS) channels can be reduced to a small number of system-specific parameters.
FRONTIERS IN PHYSIOLOGY
(2021)
Article
Cell Biology
Timo Smit, Esther Schickel, Omid Azimzadeh, Christine von Toerne, Oliver Rauh, Sylvia Ritter, Marco Durante, Insa S. Schroeder
Summary: This study utilized 3D aggregates of human embryonic stem cell-derived cardiomyocytes to investigate the effects of ionizing radiation and maturity levels of the cells. The matured aggregates displayed increased beat rates and more arrhythmic cellular sequences after X-ray irradiation compared to non-irradiated controls. Proteome analysis provided insight into signaling mechanisms contributing to cardiotoxicity and proposed an in vitro model for screening various noxae targeting adult cardiotoxicity.
Review
Physics, Multidisciplinary
Joao Luis Carvalho-de-Souza, Andrea Saponaro, C. A. Z. Bassetto, Oliver Rauh, Indra Schroeder, Fabio Franciolini, Luigi Catacuzzeno, Francisco Bezanilla, Gerhard Thiel, Anna Moroni
Summary: This article summarizes recent advancements in understanding the mechanisms of ion permeation and gating in channel proteins, focusing on the elementary steps of ion transport through the pore and non-canonical modes of intramolecular communication between peripheral sensory domains and the central channel pore.
ADVANCES IN PHYSICS-X
(2022)
Article
Biochemistry & Molecular Biology
Oliver Rauh, Jennifer Opper, Maximilian Sturm, Nils Drexler, Deborah D. D. Scheub, Ulf-P. Hansen, Gerhard Thiel, Indra Schroeder
Summary: Most potassium channels have two gate locations, an inner gate and a filter gate, and the function of these gates is coupled in many channels. This study focuses on the filter gate of the viral channel KcvNTS and investigates its opening and closing mechanisms through single-channel recordings and gating analysis. The results show that mutations can affect the closing speed of the filter gate, and the coupling between the filter gate and surrounding structures may rely on different modes of interaction. Quantitative analysis suggests a concerted action of subunits in the energy barrier for filter closure.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Physiology
Jan H. Krumbach, Daniel Bauer, Atiyeh Sadat Sharifzadeh, Andrea Saponaro, Rene Lautenschlaeger, Kristina Lange, Oliver Rauh, Dario DiFrancesco, Anna Moroni, Gerhard Thiel, Kay Hamacher
Summary: The authors used molecular dynamics simulations to study the interactions between monovalent cations and the HCN4 channel, and found that cation selectivity is determined by an adaptation of the cations to the filter structure. This study is important for understanding biological processes such as heartbeat and neuronal firing.
JOURNAL OF GENERAL PHYSIOLOGY
(2023)
Article
Cell Biology
Anja J. Engel, Steffen Paech, Markus Langhans, James L. van Etten, Anna Moroni, Gerhard Thiel, Oliver Rauh
Summary: When the K+ channel-like protein Kesv from Ectocarpus siliculosus virus 1 is expressed in mammalian cells, it is targeted to the mitochondria. By altering codon usage or inserting hydrophobic amino acids into the protein's C-terminal transmembrane domain, the targeting can be redirected to the endoplasmic reticulum (ER). Positive charge in the inserted amino acid triplet serves as a strong signal for mitochondria sorting, while a combination of hydrophilic amino acids and rarely used codons favors mitochondria sorting in cases of neutral amino acid triplets. Sorting to the ER is influenced by the inverse dependency. The data suggest that local changes in elongation velocity and co-translational folding in the C-terminal transmembrane domain can influence intracellular protein sorting.
Article
Biophysics
Stefano Conti Nibali, Maria Carmela Di Rosa, Oliver Rauh, Gerhard Thiel, Simona Reina, Vito De Pinto
Summary: VDAC is a key protein of the outer mitochondrial membrane in all eukaryotes, with its electrophysiological properties extensively analyzed. A one-step reaction combining in vitro cell-free protein expression with nanodisc technology has been proposed to obtain human VDAC isoforms integrated in a native-like lipid bilayer, overcoming the limitations of membrane protein overexpression. Membrane-mimicking nanodisc systems represent a breakthrough in VDAC electrophysiology and may be utilized for further structural studies.
BIOPHYSICAL REPORTS
(2021)
Article
Biophysics
Michael Schmidt, Indra Schroeder, Daniel Bauer, Gerhard Thiel, Kay Hamacher
Summary: Coarse-grained protein models approximate physical potentials through relative entropy framework, which adjusts model parameters by minimizing entropy to maximize likelihood of reproducing observations. This study extends the optimization process to identify optimal mappings to dimension-reduced topologies, evaluating findings by comparing anisotropic network models of ion channels to experimental results.
EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Denise Eckert, Tobias Schulze, Julian Stahl, Oliver Rauh, James L. Van Etten, Brigitte Hertel, Indra Schroeder, Anna Moroni, Gerhard Thiel