scholarly journals Quaternary structure independent folding of voltage-gated ion channel pore domain subunits

2021 ◽  
Author(s):  
Cristina Arrigoni ◽  
Marco Lolicato ◽  
David Shaya ◽  
Ahmed Rohaim ◽  
Felix Findeisen ◽  
...  
Keyword(s):  
Ion Channel ◽  
Tertiary Structure ◽  
Quaternary Structure ◽  
Transmembrane Helix ◽  
Full Length ◽  
Structural Element ◽  
Voltage Gated ◽  
Evolutionary Origins ◽  
Ion Conducting ◽  
Pore Domain

Every voltage-gated ion channel (VGIC) superfamily member has an ion conducting pore consisting of four pore domain (PD) subunits that are each built from a common plan comprising an antiparallel transmembrane helix pair, a short, obliquely positioned helix (the pore helix), and selectivity filter. The extent to which this structure, the VGIC-PD fold, relies on the extensive quaternary interactions observed in PD assemblies is unclear. Here, we present crystal structures of three bacterial voltage-gated sodium channel (BacNaV) pores that adopt a surprising set of non canonical quaternary structures and yet maintain the native tertiary structure of the PD monomer. This context-independent structural robustness demonstrates that the VGIC-PD fold, the fundamental VGIC structural building block, can adopt its native-like tertiary fold independent of native quaternary interactions. In line with this observation, we find that the VGIC PD fold is not only present throughout the VGIC superfamily and other channel classes but has homologs in diverse transmembrane and soluble proteins. Characterization of the structures of two synthetic Fabs (sFabs) that recognize the VGIC PD fold shows that such sFabs can bind purified full-length channels and indicates that non-canonical quaternary PD assemblies can occur in the context of complete VGICs. Together, our data demonstrate that the VGIC-PD structure can fold independently of higher order assembly interactions and suggest that full length VGIC PDs can access previously unknown non-canonical quaternary states. These PD properties have deep implications for understanding how the complex quaternary architectures of VGIC superfamily members are achieved and point to possible evolutionary origins of this fundamental VGIC structural element.

scholarly journals The isolated voltage sensing domain of the Shaker potassium channel forms a voltage-gated cation channel

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Juan Zhao ◽  
Rikard Blunck
Keyword(s):  
Transmembrane Helix ◽  
Voltage Sensing ◽  
Shaker Potassium Channel ◽  
Voltage Gated ◽  
Kv Channel ◽  
C Terminus ◽  
Ion Conducting ◽  
Voltage Gated Ion Channels ◽  
Voltage Sensing Domain ◽  
Pore Domain

Domains in macromolecular complexes are often considered structurally and functionally conserved while energetically coupled to each other. In the modular voltage-gated ion channels the central ion-conducting pore is surrounded by four voltage sensing domains (VSDs). Here, the energetic coupling is mediated by interactions between the S4-S5 linker, covalently linking the domains, and the proximal C-terminus. In order to characterize the intrinsic gating of the voltage sensing domain in the absence of the pore domain, the Shaker Kv channel was truncated after the fourth transmembrane helix S4 (Shaker-iVSD). Shaker-iVSD showed significantly altered gating kinetics and formed a cation-selective ion channel with a strong preference for protons. Ion conduction in Shaker-iVSD developed despite identical primary sequence, indicating an allosteric influence of the pore domain. Shaker-iVSD also displays pronounced 'relaxation'. Closing of the pore correlates with entry into relaxation suggesting that the two processes are energetically related.

scholarly journals Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors

2018 ◽  
Vol 150 (8) ◽  
pp. 1215-1230 ◽  
Author(s):  
Sara I. Liin ◽  
Per-Eric Lund ◽  
Johan E. Larsson ◽  
Johan Brask ◽  
Björn Wallner ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Action Potential ◽  
Ion Channel ◽  
Potassium Channel ◽  
Voltage Sensor ◽  
Pharmaceutical Drugs ◽  
Voltage Gated ◽  
Channel Opening ◽  
Ion Conducting ◽  
Voltage Gated Ion Channels

Voltage-gated ion channels are key molecules for the generation of cellular electrical excitability. Many pharmaceutical drugs target these channels by blocking their ion-conducting pore, but in many cases, channel-opening compounds would be more beneficial. Here, to search for new channel-opening compounds, we screen 18,000 compounds with high-throughput patch-clamp technology and find several potassium-channel openers that share a distinct biaryl-sulfonamide motif. Our data suggest that the negatively charged variants of these compounds bind to the top of the voltage-sensor domain, between transmembrane segments 3 and 4, to open the channel. Although we show here that biaryl-sulfonamide compounds open a potassium channel, they have also been reported to block sodium and calcium channels. However, because they inactivate voltage-gated sodium channels by promoting activation of one voltage sensor, we suggest that, despite different effects on the channel gates, the biaryl-sulfonamide motif is a general ion-channel activator motif. Because these compounds block action potential–generating sodium and calcium channels and open an action potential–dampening potassium channel, they should have a high propensity to reduce excitability. This opens up the possibility to build new excitability-reducing pharmaceutical drugs from the biaryl-sulfonamide scaffold.

scholarly journals Consensus channelome of dinoflagellates revealed by transcriptomic analysis sheds light on their physiology

ALGAE ◽  
2021 ◽  
Vol 36 (4) ◽  
pp. 315-326
Author(s):  
Ilya Pozdnyakov ◽  
Olga Matantseva ◽  
Sergei Skarlato
Keyword(s):  
Ion Channels ◽  
Potassium Channels ◽  
Ion Channel ◽  
Chloride Channels ◽  
Cation Channels ◽  
Mechanosensitive Channels ◽  
Anion Channels ◽  
Voltage Gated ◽  
Calcium Activated Potassium Channels ◽  
Pore Domain

Ion channels are membrane protein complexes mediating passive ion flux across the cell membranes. Every organism has a certain set of ion channels that define its physiology. Dinoflagellates are ecologically important microorganisms characterized by effective physiological adaptability, which backs up their massive proliferations that often result in harmful blooms (red tides). In this study, we used a bioinformatics approach to identify homologs of known ion channels that belong to 36 ion channel families. We demonstrated that the versatility of the dinoflagellate physiology is underpinned by a high diversity of ion channels including homologs of animal and plant proteins, as well as channels unique to protists. The analysis of 27 transcriptomes allowed reconstructing a consensus ion channel repertoire (channelome) of dinoflagellates including the members of 31 ion channel families: inwardly-rectifying potassium channels, two-pore domain potassium channels, voltage-gated potassium channels (Kv), tandem Kv, cyclic nucleotide-binding domain-containing channels (CNBD), tandem CNBD, eukaryotic ionotropic glutamate receptors, large-conductance calcium-activated potassium channels, intermediate/small-conductance calcium-activated potassium channels, eukaryotic single-domain voltage-gated cation channels, transient receptor potential channels, two-pore domain calcium channels, four-domain voltage-gated cation channels, cation and anion Cys-loop receptors, small-conductivity mechanosensitive channels, large-conductivity mechanosensitive channels, voltage-gated proton channels, inositole-1,4,5- trisphosphate receptors, slow anion channels, aluminum-activated malate transporters and quick anion channels, mitochondrial calcium uniporters, voltage-dependent anion channels, vesicular chloride channels, ionotropic purinergic receptors, animal volage-insensitive cation channels, channelrhodopsins, bestrophins, voltage-gated chloride channels H+/Cl- exchangers, plant calcium-permeable mechanosensitive channels, and trimeric intracellular cation channels. Overall, dinoflagellates represent cells able to respond to physical and chemical stimuli utilizing a wide range of Gprotein coupled receptors- and Ca2+-dependent signaling pathways. The applied approach not only shed light on the ion channel set in dinoflagellates, but also provided the information on possible molecular mechanisms underlying vital cellular processes dependent on the ion transport.

scholarly journals In silico characterization and structural modeling of bacterial metalloprotease of family M4

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Rajnee Hasan ◽  
Md. Nazmul Haq Rony ◽  
Rasel Ahmed
Keyword(s):  
Drug Targets ◽  
Active Sites ◽  
Pathogenic Bacteria ◽  
Tertiary Structure ◽  
Transmembrane Helix ◽  
Confidence Score ◽  
Potential Drug ◽  
Protein Protein Interaction ◽  
Industrial Level ◽  
Potential Drug Targets

Abstract Background The M4 family of metalloproteases is comprised of a large number of zinc-containing metalloproteases. A large number of these enzymes are important virulence factors of pathogenic bacteria and therefore potential drug targets. Whereas some enzymes have potential for biotechnological applications, the M4 family of metalloproteases is known almost exclusively from bacteria. The aim of the study was to identify the structure and properties of M4 metalloprotease proteins. Results A total of 31 protein sequences of M4 metalloprotease retrieved from UniProt representing different species of bacteria have been characterized for various physiochemical properties. They were thermostable, hydrophillic protein of a molecular mass ranging from 38 to 66 KDa. Correlation on the basis of both enzymes and respective genes has also been studied by phylogenetic tree. B. cereus M4 metalloprotease (PDB ID: 1NPC) was selected as a representative species for secondary and tertiary structures among the M4 metalloprotease proteins. The secondary structure displaying 11 helices (H1-H11) is involved in 15 helix-helix interactions, while 4 β-sheet motifs composed of 15 β-strands in PDBsum. Possible disulfide bridges were absent in most of the cases. The tertiary structure of B. cereus M4 metalloprotease was validated by QMEAN4 and SAVES server (Ramachandran plot, verify 3D, and ERRAT) which proved the stability, reliability, and consistency of the tertiary structure of the protein. Functional analysis was done in terms of membrane protein topology, disease-causing region prediction, proteolytic cleavage sites prediction, and network generation. Transmembrane helix prediction showed absence of transmembrane helix in protein. Protein-protein interaction networks demonstrated that bacillolysin of B. cereus interacted with ten other proteins in a high confidence score. Five disorder regions were identified. Active sites analysis showed the zinc-binding residues—His-143, His-147, and Glu-167, with Glu-144 acting as the catalytic residues. Conclusion Moreover, this theoretical overview will help researchers to get a details idea about the protein structure and it may also help to design enzymes with desirable characteristics for exploiting them at industrial level or potential drug targets.

scholarly journals Transmitter and ion channel profiles of neurons in the primate abducens and trochlear nuclei

2021 ◽  
Author(s):  
Ümit Suat Mayadali ◽  
Jérome Fleuriet ◽  
Michael Mustari ◽  
Hans Straka ◽  
Anja Kerstin Ellen Horn
Keyword(s):  
Eye Movements ◽  
Ion Channel ◽  
Membrane Properties ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Voltage Gated ◽  
Calcium Ion Channels ◽  
Cell Type Specific ◽  
Transmitter Receptors ◽  
Intrinsic Membrane Properties

AbstractExtraocular motoneurons initiate dynamically different eye movements, including saccades, smooth pursuit and vestibulo-ocular reflexes. These motoneurons subdivide into two main types based on the structure of the neuro-muscular interface: motoneurons of singly-innervated (SIF), and motoneurons of multiply-innervated muscle fibers (MIF). SIF motoneurons are thought to provoke strong and brief/fast muscle contractions, whereas MIF motoneurons initiate prolonged, slow contractions. While relevant for adequate functionality, transmitter and ion channel profiles associated with the morpho-physiological differences between these motoneuron types, have not been elucidated so far. This prompted us to investigate the expression of voltage-gated potassium, sodium and calcium ion channels (Kv1.1, Kv3.1b, Nav1.6, Cav3.1–3.3, KCC2), the transmitter profiles of their presynaptic terminals (vGlut1 and 2, GlyT2 and GAD) and transmitter receptors (GluR2/3, NMDAR1, GlyR1α) using immunohistochemical analyses of abducens and trochlear motoneurons and of abducens internuclear neurons (INTs) in macaque monkeys. The main findings were: (1) MIF and SIF motoneurons express unique voltage-gated ion channel profiles, respectively, likely accounting for differences in intrinsic membrane properties. (2) Presynaptic glutamatergic synapses utilize vGlut2, but not vGlut1. (3) Trochlear motoneurons receive GABAergic inputs, abducens neurons receive both GABAergic and glycinergic inputs. (4) Synaptic densities differ between MIF and SIF motoneurons, with MIF motoneurons receiving fewer terminals. (5) Glutamatergic receptor subtypes differ between MIF and SIF motoneurons. While NMDAR1 is intensely expressed in INTs, MIF motoneurons lack this receptor subtype entirely. The obtained cell-type-specific transmitter and conductance profiles illuminate the structural substrates responsible for differential contributions of neurons in the abducens and trochlear nuclei to eye movements.

scholarly journals Outer Pore Domain of TRPV1 Ion Channel is Required for Temperature-Independent Step During Temperature-Activation

2010 ◽  
Vol 98 (3) ◽  
pp. 227a
Author(s):  
Jorg Grandl ◽  
Sung Eun Kim ◽  
Valerie Uzzell ◽  
Badry Bursulaya ◽  
Matt Petrus ◽  
...  
Keyword(s):  
Ion Channel ◽  
Outer Pore ◽  
Temperature Activation ◽  
Pore Domain

scholarly journals Proton Sensors in the Pore Domain of the Cardiac Voltage-gated Sodium Channel

2013 ◽  
Vol 288 (7) ◽  
pp. 4782-4791 ◽  
Author(s):  
David K. Jones ◽  
Colin H. Peters ◽  
Charlene R. Allard ◽  
Tom W. Claydon ◽  
Peter C. Ruben
Keyword(s):  
Sodium Channel ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Pore Domain

scholarly journals Identification of a translocated gating charge in a voltage-dependent channel. Colicin E1 channels in planar phospholipid bilayer membranes.

1991 ◽  
Vol 98 (1) ◽  
pp. 77-93 ◽  
Author(s):  
C K Abrams ◽  
K S Jakes ◽  
A Finkelstein ◽  
S L Slatin
Keyword(s):  
Voltage Dependence ◽  
Ion Selectivity ◽  
Lipid Vesicles ◽  
Voltage Gating ◽  
Site Directed Mutagenesis ◽  
Phospholipid Bilayer ◽  
Voltage Gated ◽  
Colicin E1 ◽  
Gating Charge ◽  
Ion Conducting

The availability of primary sequences for ion-conducting channels permits the development of testable models for mechanisms of voltage gating. Previous work on planar phospholipid bilayers and lipid vesicles indicates that voltage gating of colicin E1 channels involves translocation of peptide segments of the molecule into and across the membrane. Here we identify histidine residue 440 as a gating charge associated with this translocation. Using site-directed mutagenesis to convert the positively charged His440 to a neutral cysteine, we find that the voltage dependence for turn-off of channels formed by this mutant at position 440 is less steep than that for wild-type channels; the magnitude of the change in voltage dependence is consistent with residue 440 moving from the trans to the cis side of the membrane in association with channel closure. The effect of trans pH changes on the ion selectivity of channels formed by the carboxymethylated derivative of the cysteine 440 mutant independently establishes that in the open channel state, residue 440 lies on the trans side of the membrane. On the basis of these results, we propose that the voltage-gated opening of colicin E1 channels is accompanied by the insertion into the bilayer of a helical hairpin loop extending from residue 420 to residue 459, and that voltage-gated closing is associated with the extrusion of this loop from the interior of the bilayer back to the cis side.

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