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| Open AccessStructure of a bacterial voltage-gated sodium channel pore reveals mechanisms of opening and closing
Sodium-gated ion channels open and close in response to the flow of ions. Here, McCusker et al.report the open structure of a sodium-gated ion channel pore from a bacterial homologue, and show, by comparison with the closed structure, that the movement of a C-terminal helix is sufficient to open the channel.
- Emily C. McCusker
- , Claire Bagnéris
- & B.A. Wallace
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Article |
Sound-induced length changes in outer hair cell stereocilia
In the inner ear, sound waves produce movements in hair cell sterocilia, triggering the opening of ion channels. Hakizimana and colleagues show that the resultant currents change the length of sterocilia, and that these length changes alter the efficiency by which sound is converted into electrical signals.
- Pierre Hakizimana
- , William E. Brownell
- & Anders Fridberger
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Article
| Open AccessEfficacy of the β2-adrenergic receptor is determined by conformational equilibrium in the transmembrane region
Many drugs exist that target the β-adrenergic receptor, but they have different efficacies. Kofukuet al. use NMR to show that methionine 82 in the transmembrane domain undergoes conformational changes depending on whether agonists or inverse agonists are bound, explaining the differential drug efficacy.
- Yutaka Kofuku
- , Takumi Ueda
- & Ichio Shimada
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Article
| Open AccessThe allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling
Class A seven transmembrane helical receptors harbour vestibules at the entrance to the ligand-binding domain. Here, Bocket al. use probes to monitor the conformation of the M2 muscarinic receptor and show that the vestibule alters the extent of receptor movement.
- Andreas Bock
- , Nicole Merten
- & Klaus Mohr
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Rotational dynamics of cargos at pauses during axonal transport
Vesicle trafficking in the cell is likely to involve a tug-of-war between motor proteins of opposing directionality. Guet al. use high-speed single-particle tracking in neurons to uncover rotation of paused cargo vesicles, providing insight into the changing forces as the vesicles change direction.
- Yan Gu
- , Wei Sun
- & Ning Fang
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Article
| Open AccessControlled rotation of the F1-ATPase reveals differential and continuous binding changes for ATP synthesis
Reverse rotation of the F1-ATPase results in the synthesis, rather than hydrolysis of ATP. Adachiet al. show that the molecular mechanism of ATP synthesis is the reverse of hydrolysis-driven rotation of the motor, and that ADP and ATP are discriminated by angle-dependent binding.
- Kengo Adachi
- , Kazuhiro Oiwa
- & Kazuhiko Kinosita Jr
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Imaging enzyme-triggered self-assembly of small molecules inside live cells
Supramolecular interactions allow some small molecules to self-assemble into nanofibres and hydrogels in aqueous environments. Gaoet al.report a hydrogelator that forms fluorescent nanofibres within cells, leading to the visualization of their self-assembly at the endoplasmic reticulum.
- Yuan Gao
- , Junfeng Shi
- & Bing Xu
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Protein sliding and DNA denaturation are essential for DNA organization by human mitochondrial transcription factor A
The mitochondrial transcription factor A (TFAM) mediates both mitochondrial transcription and DNA compaction, but how it achieves these two functions is unknown. In this study, TFAM is shown to slide along DNA and cause local melting, suggesting a mechanism for how TFAM modulates both transcription and compaction.
- Géraldine Farge
- , Niels Laurens
- & Gijs J.L. Wuite
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Article
| Open AccessDistant residues mediate picomolar binding affinity of a protein cofactor
Flavodoxin requires tight binding of its FMN cofactor to be active, but the residues involved are unknown. In this biophysical study, FMN binding is shown to change from nanomolar to picomolar affinity on extremely slow protein relaxation and the residues responsible for cofactor binding are identified.
- Yves J.M. Bollen
- , Adrie H. Westphal
- & Carlo P.M. van Mierlo
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Evidence for activity-regulated hormone-binding cooperativity across glycoprotein hormone receptor homomers
Glycoprotein hormone receptors show negative cooperativity following a single molecule of agonist binding to each receptor dimer. Here, constitutively active receptors are shown to display less cooperative allosteric regulation, suggesting a direct relationship between conformational changes in the transmembrane domain and allosteric behaviour of the receptor dimers.
- Maxime Zoenen
- , Eneko Urizar
- & Sabine Costagliola
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TREX exposes the RNA-binding domain of Nxf1 to enable mRNA export
The TREX complex and Nxf1 are involved in the export of mRNA from the nucleus but the precise molecular function of TREX is unclear. Here, the TREX components Aly and Thoc5 are shown to bind to Nxf1 resulting in a change in Nxf1 conformation that permits binding to mRNA and nuclear export.
- Nicolas Viphakone
- , Guillaume M. Hautbergue
- & Stuart A. Wilson
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Mechanism of resilin elasticity
Resilin is a polymeric elastic protein that is important for the flight and jumping of insects. Here, the structure-function relationships ofDrosophilaresilin are investigated, and a mechanical model is proposed to account for its elasticity.
- Guokui Qin
- , Xiao Hu
- & David L. Kaplan
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Controlled delivery of bioactive molecules into live cells using the bacterial mechanosensitive channel MscL
The bacterial channel protein MscL opens in response to mechanical forces and could be exploited for vesicular-based drug delivery. Doerneret al. show that functional MscL can be expressed in mammalian cells and facilitate the controlled cellular uptake of relatively large, membrane-impermeable bioactive molecules.
- Julia F. Doerner
- , Sebastien Febvay
- & David E. Clapham
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Article
| Open AccessDistinct loops in arrestin differentially regulate ligand binding within the GPCR opsin
Following retinalcis/trans isomerisation, the active form of the G-protein-coupled receptor rhodopsin decays to opsin and all-trans-retinal. In this study, arrestin, a regulator of G-protein-coupled receptor activity, is shown to facilitate the concurrent sequestering of toxic all-trans-retinal and regeneration of 11-cis-retinal within the opsin population.
- Martha E. Sommer
- , Klaus Peter Hofmann
- & Martin Heck
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Gating of cyclic nucleotide-gated channels is voltage dependent
Cyclic nucleotide-gated channels are apparently voltage insensitive despite having the S4-type voltage sensor. Marchesiet al.show that the gating of wild-type CNGA1 and native CNG channels is voltage-independent in the presence of Li+, Na+ and K+, but that it is voltage-dependent in the presence of Rb+, Cs+ and organic cations.
- Arin Marchesi
- , Monica Mazzolini
- & Vincent Torre
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Article
| Open AccessSwitching of myosin-V motion between the lever-arm swing and Brownian search-and-catch
The motor protein myosin-V transports cargo along actin filaments, but the biophysical mechanisms by which myosin-V generates force are unclear. Here, optical tweezers and a DNA handle are used to study the forces generated by myosin-V: the mechanism of force generation is found to depend on the load applied.
- Keisuke Fujita
- , Mitsuhiro Iwaki
- & Toshio Yanagida
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Histone modifications and lamin A regulate chromatin protein dynamics in early embryonic stem cell differentiation
Chromatin in embryonic stem cells is present in an open state presumably to facilitate gene expression changes required for pluripotency and subsequent multilineage differentiation. This study describes roles for lamin A, histone acetylation and G9a-mediated histone H3 lysine 9 methylation in regulating chromatin plasticity in these cells.
- Shai Melcer
- , Hadas Hezroni
- & Eran Meshorer
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Crystal structure of a plectonemic RNA supercoil
Nucleic acid superstructures are required to package genomes into the nucleus of cells. In this study, the superstructure of an RNA supercoil species is reported and is shown to be dependent on an RNA-binding protein that induces a higher level of organization compared with DNA superstructures.
- Jason R. Stagno
- , Buyong Ma
- & Xinhua Ji
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Prediction of variable translation rate effects on cotranslational protein folding
Proteins can undergo folding while being translated by the ribosome, and the extent of this folding is influenced by the rate at which amino acids are added to the nascent chain. This study provides a framework for predicting domain folding probabilities as a function of the kinetics of amino-acid addition.
- Edward P. O'Brien
- , Michele Vendruscolo
- & Christopher M. Dobson
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Assembly kinetics determine the architecture of α-actinin crosslinked F-actin networks
Processes that regulate the mechanical and dynamic properties of actin cytoskeleton are important for multiple eukaryotic cell functions. In this study, using reconstituted crosslinked actin networks, organization is found to be determined by the competing kinetics of actin gelation and bundle formation.
- Tobias T. Falzone
- , Martin Lenz
- & Margaret L. Gardel
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Article
| Open AccessThe Dishevelled-associating protein Daple controls the non-canonical Wnt/Rac pathway and cell motility
The non-canonical Wnt signalling pathway mediates cell migration via the GTPase Rac but the detailed mechanism is unclear. In this study, the Daple protein is shown to regulate Wnt5a mediated activation of Rac, resulting in the formation of lamellipodia and cell migration.
- Maki Ishida-Takagishi
- , Atsushi Enomoto
- & Masahide Takahashi
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Dynamic force-induced direct dissociation of protein complexes in a nuclear body in living cells
Cells can sense their local environment by a process termed mechanotransduction, but whether these signals are relayed to the nucleus is unclear. This study demonstrates that a force applied at the cell surface can alter the localization of proteins within Cajal bodies that are found in the nuclear compartment.
- Yeh-Chuin Poh
- , Sergey P. Shevtsov
- & Ning Wang
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Microtubule and cortical forces determine platelet size during vascular platelet production
Platelets are formed from megakaryocytes but the exact mechanisms are unknown. Thonet al.describe circular preplatelets and barbell shaped proplatelets in human blood and demonstrate, with the aid of a mathematical model, a role for microtubule-based forces in regulating final platelet size.
- Jonathan N Thon
- , Hannah Macleod
- & Joseph E. Italiano Jr
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Article
| Open AccessThe cytoplasmic coiled-coil mediates cooperative gating temperature sensitivity in the voltage-gated H+ channel Hv1
In the dimeric voltage-gated H+channel, Hv1/VSOP, the gating of each subunit is coupled, but the molecular basis of dimer formation and intersubunit coupling is unclear. This study shows that channel assembly and cooperative gating are mediated by the cytoplasmic domain.
- Yuichiro Fujiwara
- , Tatsuki Kurokawa
- & Yasushi Okamura
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| Open AccessThe C-terminal helical bundle of the tetrameric prokaryotic sodium channel accelerates the inactivation rate
Many channels have cytosolic domains which regulate channel function. Irieet al. show that the cytosolic C-terminal region of NavSulP, a prokaryotic voltage-gated sodium channel, forms a four-helix bundle which stabilises the tetrameric channel and accelerates channel inactivation.
- Katsumasa Irie
- , Takushi Shimomura
- & Yoshinori Fujiyoshi
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Nanodomain Ca2+ of Ca2+ channels detected by a tethered genetically encoded Ca2+ sensor
Calcium nanodomains arise from the cytoplasmic mouth of calcium channels but have not been directly visualized. In this study, the nanodomain of the CaV2.2 calcium channel is imaged using total internal reflection fluorescence microscopy and a genetically encoded calcium sensor attached to the carboxy terminus.
- Lai Hock Tay
- , Ivy E. Dick
- & David T. Yue
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Article
| Open AccessInfrared light excites cells by changing their electrical capacitance
Pulsed infrared laser light can directly stimulate nerves and muscles, but the underlying biophysical mechanism has remained enigmatic. This study reveals that infrared pulses depolarize target cells by reversibly altering the electrical capacitance of the plasma membrane.
- Mikhail G. Shapiro
- , Kazuaki Homma
- & Francisco Bezanilla
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Article
| Open AccessIntracellular chloride concentration influences the GABAA receptor subunit composition
During development there is a change in the expression of GABAA receptor subunits. Here, Succol and colleagues show that chloride ions mediate the change in α3-α1 and δ-containing GABAAreceptors that mediate phasic and tonic inhibition, respectively.
- Francesca Succol
- , Hubert Fiumelli
- & Andrea Barberis
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Dimensional and temporal controls of three-dimensional cell migration by zyxin and binding partners
Molecular and oscillations are common in biology, but periodic cell migrations have not been observed. Fraleyet al. report regular, periodic migrations of cells along tracks generated inside 3D matrices, and show that these 1D oscillations are controlled by zyxin and its binding partners α-actinin and p130Cas.
- Stephanie I. Fraley
- , Yunfeng Feng
- & Denis Wirtz
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Perturbation of sodium channel structure by an inherited Long QT Syndrome mutation
Perturbation of the cardiac voltage-gated sodium channel, NaV1.5, by drugs or inherited mutation can underlie and trigger cardiac arrhythmias. Here, the role of the NaV1.5 carboxy terminus in channel inactivation is investigated, and structural details of an arrhythmia associated H6 mutant are reported.
- Ian W. Glaaser
- , Jeremiah D. Osteen
- & Robert S. Kass
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Article
| Open AccessThe dynamic stator stalk of rotary ATPases
The peripheral stalks of rotary ATPases counteract torque generated by rotation of the central stalk during ATP synthesis or hydrolysis. Stewartet al.report the crystal structure of an A-type ATPase/synthase peripheral stalk and identify bending and twisting motions that permit the radial wobbling of the headgroup.
- Alastair G. Stewart
- , Lawrence K. Lee
- & Daniela Stock
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| Open AccessThe dynamic relationships between the three events that release individual Na+ ions from the Na+/K+-ATPase
The Na+/K+-ATPase pump exports three Na+ ions for the exchange of two K+ ions, and three transient current components have been associated with Na+ binding and release. Now, these three components are found to be tightly correlated confirming that the binding and release of Na+ions is sequential.
- David C. Gadsby
- , Francisco Bezanilla
- & Miguel Holmgren
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Spatial coordination between cell and nuclear shape within micropatterned endothelial cells
Actin filaments are involved in the modulation of nuclear shape and function, but mechanistic understanding of these processes is lacking. Versaevelet al. show that orientation and deformation of the nucleus are regulated by lateral compressive forces driven by tension in central actomyosin fibres.
- Marie Versaevel
- , Thomas Grevesse
- & Sylvain Gabriele
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Article
| Open AccessELL facilitates RNA polymerase II pause site entry and release
The super elongation complex, which is involved in transcriptional elongation, contains the Eleven-nineteen Lysine-rich Leukemia protein (ELL). In this study, ELL is shown to stabilize RNA polymerase II prior to recruitment into the super elongation complex, suggesting ELL has a role in early transcription elongation.
- Jung S. Byun
- , Temesgen D. Fufa
- & Kevin Gardner
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Two rotating cilia in the node cavity are sufficient to break left–right symmetry in the mouse embryo
The left–right asymmetry of an organism is patterned during development and is determined by fluid flow created by the movement of cilia. In this study, the asymmetry is shown to be determined early after the movement of cilia is established and that only two rotating cilia are required for breaking symmetry.
- Kyosuke Shinohara
- , Aiko Kawasumi
- & Hiroshi Hamada
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Structural rearrangements underlying ligand-gating in Kir channels
Inward rectifier potassium channels are regulated by a range of ligands that act on a common gate, but the structural details of gating are unclear. Here, the molecular motions associated with gating of KirBac1.1 channels are assessed using small molecule fluorescent probes attached to introduced cysteines.
- Shizhen Wang
- , Sun-Joo Lee
- & Colin G. Nichols
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Article
| Open AccessExtrasynaptic vesicle recycling in mature hippocampal neurons
In the classical model, fast neuronal signalling occurs at specialized presynaptic terminals. Now, Ratnayakaet al. show that stimulus-driven fusion and recycling of synaptic vesicles can occur at axonal sites remote from conventional synapses. These findings have implications for dynamic forms of neuron–neuron communication.
- Arjuna Ratnayaka
- , Vincenzo Marra
- & Kevin Staras
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Super-resolution surface mapping using the trajectories of molecular probes
Surface characterization of soft materialsin situis challenging due to the importance of non-covalent interactions. Now, a new chemical imaging method is reported that generates images of surface interactions by combining many molecular probe trajectories.
- Robert Walder
- , Nathaniel Nelson
- & Daniel K. Schwartz
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Review Article |
Integrating the biophysical and molecular mechanisms of auditory hair cell mechanotransduction
Hair cells of the inner ear transduce vibrations of the basilar membrane into electrical signals by a process known as mechanotransduction. Recent advances in genetic and molecular tools have led to an improved understanding of mechanotransduction as Peng and colleagues summarize in this Review.
- Anthony W. Peng
- , Felipe T. Salles
- & Anthony J. Ricci
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NMDA receptor activation requires remodelling of intersubunit contacts within ligand-binding heterodimers
In non-NMDA glutamate receptors, intersubunit contacts within agonist binding domains affect functional desensitization. Now, NMDA receptor activation, but not desensitization, is shown to involve rearrangements at the heterodimer interface, suggesting that the intersubunit contacts of NMDA and non-NMDA receptors may have distinct functional roles.
- William F. Borschel
- , Swetha E. Murthy
- & Gabriela K. Popescu
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Single-molecule fluorescence spectroscopy maps the folding landscape of a large protein
The folding of multidomain proteins can involve metastable intermediate states. Here, a single-molecule FRET based method is developed and used to identify six metastable states in the folding landscape of the three-domain protein adenylate kinase.
- Menahem Pirchi
- , Guy Ziv
- & Gilad Haran
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Review Article |
Capturing the essence of folding and functions of biomolecules using coarse-grained models
Coarse-grained models can be used to study the folding of biological macromolecules such as DNA, RNA and proteins. In this Review, Hyeon and Thirumalai describe recent advances in the use of these theoretical models to describe dynamic processes in biology.
- Changbong Hyeon
- & D. Thirumalai
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Article
| Open AccessAn energy transduction mechanism used in bacterial flagellar type III protein export
A bacterial export gate complex transports flagellar proteins across the cytoplasmic membrane, but the mechanism of this process is unclear. Here, the export gate complex is revealed as a proton–protein antiporter that uses separate components of the proton motive force for different steps of the export process.
- Tohru Minamino
- , Yusuke V. Morimoto
- & Keiichi Namba
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Article
| Open AccessBackbone rigidity and static presentation of guanidinium groups increases cellular uptake of arginine-rich cell-penetrating peptides
Cell-penetrating peptides can deliver molecular cargoes into living cells, and cross biological membranes by transduction—a non-endocytic mechanism. Here, the transduction efficiency of cyclic arginine-rich peptides is shown to be higher than that of more flexible linear peptides.
- Gisela Lättig-Tünnemann
- , Manuel Prinz
- & M. Cristina Cardoso
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Article
| Open AccessMolecular mechanism for 3:1 subunit stoichiometry of rod cyclic nucleotide-gated ion channels
The assembly mechanisms of heteromeric ion channels are poorly understood. Using a range of techniques, Shuartet al.determine the mechanism by which rod photoreceptor cyclic nucleotide-gated channels assume a 3:1 stoichiometry of CNGA1 and CNGB1 subunits.
- Noah G. Shuart
- , Yoni Haitin
- & William N. Zagotta
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Direct visualization of microtubules using a genetic tool to analyse radial progenitor-astrocyte continuum in brain
The development of radial progenitor cells and astroglia in the cerebral cortex depends on the microtubule cytoskeleton. Eomet al. have developed a new mouse model where the microtubules of astrocytes and radial glia cells are fluorescently tagged, facilitating the detailed study of microtubule dynamics and development in these cells.
- Tae-Yeon Eom
- , Amelia Stanco
- & E.S. Anton
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Article
| Open AccessFreely orbiting magnetic tweezers to directly monitor changes in the twist of nucleic acids
Rotational motion and torsional strain affects DNA replication, transcription and repair. Lipfertet al. have developed a new technique that uses freely orbiting magnetic tweezers to measure equilibrium fluctuations and determine the twist of tethered nucleic acid molecules.
- Jan Lipfert
- , Matthew Wiggin
- & Nynke H. Dekker
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Article
| Open AccessA CLASP-modulated cell edge barrier mechanism drives cell-wide cortical microtubule organization in Arabidopsis
How microtubules are organized correctly in plant cells is not well understood. Ambroseet al. use 4D imaging and computer modelling to show that sharp cell edges induce microtubule depolymerization and that the microtubule-associated protein CLASP mitigates this process to modulate array organization.
- Chris Ambrose
- , Jun F. Allard
- & Geoffrey O. Wasteneys
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Article
| Open AccessEditing of human KV1.1 channel mRNAs disrupts binding of the N-terminus tip at the intracellular cavity
RNA editing is important in regulating neuronal excitability, and a specific editing event has been shown to alter the permeation pathway of voltage-gate potassium channels. Gonzalezet al.find that the tip of the channel's inactivation gate makes a direct hydrophobic interaction with the edited position.
- Carlos Gonzalez
- , Angelica Lopez-Rodriguez
- & Miguel Holmgren