Selection of Inhibitor-Resistant Viral Potassium Channels Identifies a Selectivity Filter Site that Affects Barium and Amantadine Block

Chatelain, Franck C.; Gazzarrini, Sabrina; Fujiwara, Yuichiro; Arrigoni, Cristina; Domigan, Courtney; Ferrara, Giuseppina; Pantoja, Carlos; Thiel, Gerhard; Moroni, Anna; Minor, Daniel L.

doi:10.1371/journal.pone.0007496

Title: Selection of Inhibitor-Resistant Viral Potassium Channels Identifies a Selectivity Filter Site that Affects Barium and Amantadine Block

Journal Article · 16 October 2009 · PLoS ONE

DOI: https://doi.org/10.1371/journal.pone.0007496 · OSTI ID:1627387

Chatelain, Franck C. ^[1]; Gazzarrini, Sabrina ^[2]; Fujiwara, Yuichiro ^[3]; Arrigoni, Cristina ^[4]; Domigan, Courtney ^[3]; Ferrara, Giuseppina ^[4]; Pantoja, Carlos ^[5]; Thiel, Gerhard ^[6]; Moroni, Anna ^[4]; Minor, Daniel L. ^[7]

Univ. of California, San Francisco, CA (United States). Cardiovascular Research Inst.; DOE/OSTI
Univ. degli Studi di Milano (Italy). Dipartimento di Biologia e Istituto di Biofisica del Consiglio Nazionale delle Ricerche
Univ. of California, San Francisco, CA (United States). Cardiovascular Research Inst.
Univ. degli Studi di Milano (Italy). Dipartimento di Biologia e Istituto di Biofisica del Consiglio Nazionale delle Ricerche
Univ. of California, San Francisco, CA (United States). Dept. of Cellular and Molecular Pharmacology
Technical Univ. of Darmstadt (Germany). Inst. fur Botanik
Univ. of California, San Francisco, CA (United States). Dept. of Cellular and Molecular Pharmacology; Univ. of California, San Francisco, CA (United States). Dept. of Biochemistry and Biophysics; Univ. of California, San Francisco, CA (United States). Dept. of California Inst. for Quantitative Biomedical Research; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Physical Biosciences Division

Background: Understanding the interactions between ion channels and blockers remains an important goal that has implications for delineating the basic mechanisms of ion channel function and for the discovery and development of ion channel directed drugs. Methodology/Principal Findings: We used genetic selection methods to probe the interaction of two ion channel blockers, barium and amantadine, with the miniature viral potassium channel Kcv. Selection for Kcv mutants that were resistant to either blocker identified a mutant bearing multiple changes that was resistant to both. Implementation of a PCR shuffling and backcrossing procedure uncovered that the blocker resistance could be attributed to a single change, T63S, at a position that is likely to form the binding site for the inner ion in the selectivity filter (site 4). A combination of electrophysiological and biochemical assays revealed a distinct difference in the ability of the mutant channel to interact with the blockers. Studies of the analogous mutation in the mammalian inward rectifier Kir2.1 show that the TRS mutation affects barium block as well as the stability of the conductive state. Comparison of the effects of similar barium resistant mutations in Kcv and Kir2.1 shows that neighboring amino acids in the Kcv selectivity filter affect blocker binding. Conclusions/Significance: The data support the idea that permeant ions have an integral role in stabilizing potassium channel structure, suggest that both barium and amantadine act at a similar site, and demonstrate how genetic selections can be used to map blocker binding sites and reveal mechanistic features.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

OSTI ID:: 1627387

Journal Information:: PLoS ONE, Journal Name: PLoS ONE Journal Issue: 10 Vol. 4; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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A small-molecule screen in C. elegans yields a new calcium channel antagonist Kwok, Trevor C. Y.; Ricker, Nicole; Fraser, Regina Nature, Vol. 441, Issue 7089 https://doi.org/10.1038/nature04657	journal	May 2006
hERG potassium channels and cardiac arrhythmia Sanguinetti, Michael C.; Tristani-Firouzi, Martin Nature, Vol. 440, Issue 7083 https://doi.org/10.1038/nature04710	journal	March 2006
Structure prediction for the down state of a potassium channel voltage sensor Grabe, Michael; Lai, Helen C.; Jain, Monika Nature, Vol. 445, Issue 7127 https://doi.org/10.1038/nature05494	journal	December 2006
Structural basis for the function and inhibition of an influenza virus proton channel Stouffer, Amanda L.; Acharya, Rudresh; Salom, David Nature, Vol. 451, Issue 7178 https://doi.org/10.1038/nature06528	journal	January 2008
Structure and mechanism of the M2 proton channel of influenza A virus Schnell, Jason R.; Chou, James J. Nature, Vol. 451, Issue 7178 https://doi.org/10.1038/nature06531	journal	January 2008
High-throughput screening of small molecules for bioactivity and target identification in Caenorhabditis elegans Burns, Andrew R.; Kwok, Trevor C. Y.; Howard, Al Nature Protocols, Vol. 1, Issue 4 https://doi.org/10.1038/nprot.2006.283	journal	November 2006
High-throughput electrophysiology: an emerging paradigm for ion-channel screening and physiology Dunlop, John; Bowlby, Mark; Peri, Ravikumar Nature Reviews Drug Discovery, Vol. 7, Issue 4 https://doi.org/10.1038/nrd2552	journal	April 2008
Structural basis of TEA blockade in a model potassium channel Lenaeus, Michael J.; Vamvouka, Magdalini; Focia, Pamela J. Nature Structural & Molecular Biology, Vol. 12, Issue 5 https://doi.org/10.1038/nsmb929	journal	April 2005
Controlling influenza virus replication by inhibiting its proton channel Pinto, Lawrence H.; Lamb, Robert A. Mol. BioSyst., Vol. 3, Issue 1 https://doi.org/10.1039/B611613M	journal	January 2007
Searching for interesting channels: pairing selection and molecular evolution methods to study ion channel structure and function Minor, Jr, Daniel L. Molecular BioSystems, Vol. 5, Issue 8 https://doi.org/10.1039/b901708a	journal	January 2009
Chlorella virus ATCV-1 encodes a functional potassium channel of 82 amino acids Gazzarrini, Sabrina; Kang, Ming; Abenavoli, Alessandra Biochemical Journal, Vol. 420, Issue 2 https://doi.org/10.1042/BJ20090095	journal	May 2009
Small potassium ion channel proteins encoded by chlorella viruses Kang, M.; Moroni, A.; Gazzarrini, S. Proceedings of the National Academy of Sciences, Vol. 101, Issue 15 https://doi.org/10.1073/pnas.0307824100	journal	February 2004
Evolving potassium channels by means of yeast selection reveals structural elements important for selectivity Bichet, D.; Lin, Y. -F.; Ibarra, C. A. Proceedings of the National Academy of Sciences, Vol. 101, Issue 13 https://doi.org/10.1073/pnas.0401195101	journal	March 2004
Transmembrane domain length of viral K+ channels is a signal for mitochondria targeting Balss, J.; Papatheodorou, P.; Mehmel, M. Proceedings of the National Academy of Sciences, Vol. 105, Issue 34 https://doi.org/10.1073/pnas.0805709105	journal	August 2008
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DNA shuffling by random fragmentation and reassembly: in vitro recombination for molecular evolution. Stemmer, W. P. Proceedings of the National Academy of Sciences, Vol. 91, Issue 22 https://doi.org/10.1073/pnas.91.22.10747	journal	October 1994
Determination of Key Structural Requirements of a K+ Channel Pore Nakamura, Robert L.; Anderson, Julie A.; Gaber, Richard F. Journal of Biological Chemistry, Vol. 272, Issue 2 https://doi.org/10.1074/jbc.272.2.1011	journal	January 1997
Differential Roles of Blocking Ions in KirBac1.1 Tetramer Stability Wang, Shizhen; Alimi, Yewande; Tong, Ailing Journal of Biological Chemistry, Vol. 284, Issue 5 https://doi.org/10.1074/jbc.M807474200	journal	January 2009
Specific and Slow Inhibition of the Kir2.1 K+ Channel by Gambogic Acid Zaks-Makhina, Elena; Li, Hui; Grishin, Anatoly Journal of Biological Chemistry, Vol. 284, Issue 23 https://doi.org/10.1074/jbc.M901586200	journal	June 2009
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Functional Role and Affinity of Inorganic Cations in Stabilizing the Tetrameric Structure of the KcsA K+ Channel Krishnan, Manoj N.; Bingham, Jon-Paul; Lee, Siew Hwee Journal of General Physiology, Vol. 126, Issue 3 https://doi.org/10.1085/jgp.200509323	journal	August 2005
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Fast and slow gating are inherent properties of the pore module of the K+ channel Kcv Abenavoli, Alessandra; DiFrancesco, Mattia Lorenzo; Schroeder, Indra Journal of General Physiology, Vol. 134, Issue 3 https://doi.org/10.1085/jgp.200910266	journal	August 2009
Ionic Blockage of Sodium Channels in Nerve Woodhull, A. M. The Journal of General Physiology, Vol. 61, Issue 6 https://doi.org/10.1085/jgp.61.6.687	journal	June 1973
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Role of Methyl-Induced Polarization in Ion Binding Rossi, Mariana; Tkatchenko, Alexandre; Rempe, Susan B. Biophysical Journal, Vol. 106, Issue 2 https://doi.org/10.1016/j.bpj.2013.11.3011	journal	January 2014
A High-Throughput Functional Screen Identifies Small Molecule Regulators of Temperature- and Mechano-Sensitive K _2P Channels Bagriantsev, Sviatoslav N.; Ang, Kean-Hooi; Gallardo-Godoy, Alejandra ACS Chemical Biology, Vol. 8, Issue 8 https://doi.org/10.1021/cb400289x	journal	June 2013
Tethered Protein Display Identifies a Novel Kir3.2 (GIRK2) Regulator from Protein Scaffold Libraries Bagriantsev, Sviatoslav N.; Chatelain, Franck C.; Clark, Kimberly A. ACS Chemical Neuroscience, Vol. 5, Issue 9 https://doi.org/10.1021/cn5000698	journal	July 2014
The voltage-sensing domain of a phosphatase gates the pore of a potassium channel Arrigoni, Cristina; Schroeder, Indra; Romani, Giulia Journal of General Physiology, Vol. 141, Issue 3 https://doi.org/10.1085/jgp.201210940	journal	February 2013
Identification of Putative Potassium Channel Homologues in Pathogenic Protozoa Prole, David L.; Marrion, Neil V. PLoS ONE, Vol. 7, Issue 2 https://doi.org/10.1371/journal.pone.0032264	journal	February 2012
Engineering a Ca++-Sensitive (Bio)Sensor from the Pore-Module of a Potassium Channel DiFrancesco, Mattia; Gazzarrini, Sabrina; Arrigoni, Cristina Sensors, Vol. 15, Issue 3 https://doi.org/10.3390/s150304913	journal	February 2015
Genes for Membrane Transport Proteins: Not So Rare in Viruses Greiner, Timo; Moroni, Anna; Van Etten, James Viruses, Vol. 10, Issue 9 https://doi.org/10.3390/v10090456	journal	August 2018
A small viral potassium ion channel with an inherent inward rectification Eckert, Denise; Schulze, Tobias; Stahl, Julian Taylor & Francis https://doi.org/10.6084/m9.figshare.8024837.v1	text	January 2019
Exploring the Viral Channel KcvPBCV-1 Function via Computation Andersson, Alma E. V.; Kasimova, Marina A.; Delemotte, Lucie The Journal of Membrane Biology, Vol. 251, Issue 3 https://doi.org/10.1007/s00232-018-0022-2	journal	February 2018
Role of Methyl-Induced Polarization in Ion Binding Rossi, Mariana; Tkatchenko, Alexandre; Rempe, Susan B. Biophysical Journal, Vol. 106, Issue 2 https://doi.org/10.1016/j.bpj.2013.11.3011	journal	January 2014
Role of methyl-induced polarization in ion binding Rossi, M.; Tkatchenko, A.; Rempe, S. B. Proceedings of the National Academy of Sciences, Vol. 110, Issue 32 https://doi.org/10.1073/pnas.1302757110	journal	July 2013
A small viral potassium ion channel with an inherent inward rectification Eckert, Denise; Schulze, Tobias; Stahl, Julian Channels https://doi.org/10.1101/559716	posted_content	February 2019
Engineering of a light-gated potassium channel Cosentino, C.; Alberio, L.; Gazzarrini, S. Science, Vol. 348, Issue 6235 https://doi.org/10.1126/science.aaa2787	journal	May 2015
Genes for Membrane Transport Proteins: Not So Rare in Viruses Greiner, Timo; Moroni, Anna; Van Etten, James Viruses, Vol. 10, Issue 9 https://doi.org/10.3390/v10090456	journal	August 2018
Chloroviruses Van Etten, James L.; Agarkova, Irina V.; Dunigan, David D. Viruses, Vol. 12, Issue 1 https://doi.org/10.3390/v12010020	journal	December 2019
Random mutagenesis screening indicates the absence of a separate H ⁺ -sensor in the pH-sensitive Kir channels Paynter, Jennifer J.; Shang, Lijun; Bollepalli, Murali K. Channels, Vol. 4, Issue 5 https://doi.org/10.4161/chan.4.5.13006	journal	September 2010
Structural basis for ion selectivity in TMEM175 K+ channels Brunner, Janine D.; Jakob, Roman P.; Schulze, Tobias eLife Sciences Publications Ltd. https://doi.org/10.5167/uzh-186964	text	January 2020
A small viral potassium ion channel with an inherent inward rectification Eckert, Denise; Schulze, Tobias; Stahl, Julian Taylor & Francis https://doi.org/10.6084/m9.figshare.8024837	text	January 2019
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