Minimal art: Or why small viral K+ channels are good tools for understanding basic structure and function relations

Thiel, Gerhard; Baumeister, Dirk; Schroeder, Indra; Etten, James L. Van; Moroni, Anna

doi:10.1016/j.bbamem.2010.04.008

Cited by 40 publications

(53 citation statements)

References 56 publications

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“…1B). Because of their minimal size, Kcv and its homologs have proved excellent models for the elucidation of structural and functional properties of K ϩ channels, including gating and pharmacology (19,20). When expressed in Saccharomyces cerevisiae or mammalian cells, Kcv localizes to the plasma membrane, while Kesv localizes to the mitochondria (21).…”

Section: The Viral Kmentioning

confidence: 99%

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Cotranslational Intersection between the SRP and GET Targeting Pathways to the Endoplasmic Reticulum of Saccharomyces cerevisiae

Zhang

Schäffer

Wölfle

et al. 2016

Molecular and Cellular Biology

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cTargeting of transmembrane proteins to the endoplasmic reticulum (ER) proceeds via either the signal recognition particle (SRP) or the guided entry of tail-anchored proteins (GET) pathway, consisting of Get1 to -5 and Sgt2. While SRP cotranslationally targets membrane proteins containing one or multiple transmembrane domains, the GET pathway posttranslationally targets proteins containing a single C-terminal transmembrane domain termed the tail anchor. Here, we dissect the roles of the SRP and GET pathways in the sorting of homologous, two-membrane-spanning K ؉ channel proteins termed Kcv, Kesv, and Kesv-VV. We show that Kcv is targeted to the ER cotranslationally via its N-terminal transmembrane domain, while Kesv-VV is targeted posttranslationally via its C-terminal transmembrane domain, which recruits Get4-5/Sgt2 and Get3. Unexpectedly, nascent Kcv recruited not only SRP but also the Get4-5 module of the GET pathway to ribosomes. Ribosome binding of Get4-5 was independent of Sgt2 and was strongly outcompeted by SRP. The combined data indicate a previously unrecognized cotranslational interplay between the SRP and GET pathways.

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Section: The Viral Kmentioning

confidence: 99%

“…(A) Schematic representation of the K ϩ channel Kcv in the cytoplasmic membrane (20). (B) Reporter proteins.…”

Section: Figmentioning

confidence: 99%

Cotranslational Intersection between the SRP and GET Targeting Pathways to the Endoplasmic Reticulum of Saccharomyces cerevisiae

Zhang

Schäffer

Wölfle

et al. 2016

Molecular and Cellular Biology

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“…Despite their small size (frequently ,100 amino acids), viroporins in many cases have evolved to function as highly regulated ion channels, which makes them attractive minimalist models of ion conductance and ion channel evolution (Pinto et al, 1992;Stouffer et al, 2008;Thiel et al, 2011;OuYang et al, 2013;OuYang and Chou, 2014). The M2 viroporin of influenza A is a 97-amino-acid, type I transmembrane domain protein that forms a tetrameric ion channel that is proton-gated and proton-selective (Nieva et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Action of Novel Influenza A/M2 Viroporin Inhibitors Derived from Hexamethylene Amiloride

et al. 2016

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The increasing prevalence of influenza viruses with resistance to approved antivirals highlights the need for new anti-influenza therapeutics. Here we describe the functional properties of hexamethylene amiloride (HMA)-derived compounds that inhibit the wildtype and adamantane-resistant forms of the influenza A M2 ion channel. For example, 6-(azepan-1-yl)-N-carbamimidoylnicotinamide (9) inhibits amantadine-sensitive M2 currents with 3-to 6-fold greater potency than amantadine or HMA (IC 50 5 0.2 vs. 0.6 and 1.3 mM, respectively). Compound 9 competes with amantadine for M2 inhibition, and molecular docking simulations suggest that 9 binds at site(s) that overlap with amantadine binding. In addition, tert-butyl 49-(carbamimidoylcarbamoyl)-29,3-dinitro-

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“…Each monomer is made of 2 transmembrane domains, which are connected by the pore helices. [105][106][107][108] A further advantage of these channels is that members differ only by a few amino acids, but show quite different functional properties. This guides the experimenter to those residues, which are crucial for function.…”

Section: Supplementing 2-dimensional Dwell-time Analysis By the Analymentioning

confidence: 99%

“…[105][106][107][108] Their structure is that of an extremely reduced Kir channel: 2 transmembrane helices per monomer are connected by a short loop containing the consensus K C selectivity filter sequence and the characteristic pore helix. The protein does not contain any cytosolic or extracellular domains and it is fully embedded in the lipid bilayer.…”

Section: Channelmentioning

confidence: 99%

How to resolve microsecond current fluctuations in single ion channels: The power of beta distributions

Schroeder

2015

Channels

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A main ingredient for the understanding of structure/ function correlates of ion channels is the quantitative description of single-channel gating and conductance. However, a wealth of information provided from fast current fluctuations beyond the temporal resolution of the recording system is often ignored, even though it is close to the time window accessible to molecular dynamics simulations. This kind of current fluctuations provide a special technical challenge, because individual opening/closing or blocking/ unblocking events cannot be resolved, and the resulting averaging over undetected events decreases the singlechannel current. Here, I briefly summarize the history of fastcurrent fluctuation analysis and focus on the so-called "beta distributions." This tool exploits characteristics of current fluctuation-induced excess noise on the current amplitude histograms to reconstruct the true single-channel current and kinetic parameters. A guideline for the analysis and recent applications demonstrate that a construction of theoretical beta distributions by Markov Model simulations offers maximum flexibility as compared to analytical solutions.

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Minimal art: Or why small viral K+ channels are good tools for understanding basic structure and function relations

Cited by 40 publications

References 56 publications

Cotranslational Intersection between the SRP and GET Targeting Pathways to the Endoplasmic Reticulum of Saccharomyces cerevisiae

Cotranslational Intersection between the SRP and GET Targeting Pathways to the Endoplasmic Reticulum of Saccharomyces cerevisiae

Mechanisms of Action of Novel Influenza A/M2 Viroporin Inhibitors Derived from Hexamethylene Amiloride

How to resolve microsecond current fluctuations in single ion channels: The power of beta distributions

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