Pore domain outer helix contributes to both activation and inactivation of the hERG K+ channel

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dc.contributor.authorJu, Pen_AU
dc.contributor.authorPages, Gen_AU
dc.contributor.authorRiek, RPen_AU
dc.contributor.authorChen, PCen_AU
dc.contributor.authorTorres, AMen_AU
dc.contributor.authorBansal, PSen_AU
dc.contributor.authorKuyucak, Sen_AU
dc.contributor.authorKuchel, PWen_AU
dc.contributor.authorVandenberg, JIen_AU
dc.date.accessioned2009-09-29T05:05:55Zen_AU
dc.date.accessioned2010-04-30T05:04:53Zen_AU
dc.date.available2009-09-29T05:05:55Zen_AU
dc.date.available2010-04-30T05:04:53Zen_AU
dc.date.issued2009-01-09en_AU
dc.date.statistics2009-01-09en_AU
dc.description.abstractIon flow in many voltage-gated K+ channels (VGK), including the (human ether-a-go-go-related gene) hERG channel, is regulated by reversible collapse of the selectivity filter. hERG channels, however, exhibit low sequence homology to other VGKs, particularly in the outer pore helix (S5) domain, and we hypothesize that this contributes to the unique activation and inactivation kinetics in hERG K+ channels that are so important for cardiac electrical activity. The S5 domain in hERG identified by NMR spectroscopy closely corresponded to the segment predicted by bioinformatics analysis of 676 members of the VGK superfamily. Mutations to approximately every third residue, from Phe(551) to Trp(563), affected steady state activation, whereas mutations to approximately every third residue on an adjacent face and spanning the entire S5 segment perturbed inactivation, suggesting that the whole span of S5 experiences a rearrangement associated with inactivation. We refined a homology model of the hERG pore domain using constraints from the mutagenesis data with residues affecting inactivation pointing in toward S6. In this model the three residues with maximum impact on activation (W563A, F559A, and F551A) face out toward the voltage sensor. In addition, the residues that when mutated to alanine, or from alanine to valine, that did not express (Ala(561), His(562), Ala(565), Trp(568), and Ile(571)), all point toward the pore helix and contribute to close hydrophobic packing in this region of the channel. © 2009, American Society for Biochemistry and Molecular Biologyen_AU
dc.identifier.citationJu, P. C., Pages, G., Riek, R. P., Chen, P. C., Torres, A. M., Bansal, P. S., Kuyucak, S., Kuchel, P. W., & Vandenberg, J. I. (2009). Pore domain outer helix contributes to both activation and inactivation of the hERG K+ channel. Journal of Biological Chemistry, 284(2), 1000-1008. doi:10.1074/jbc.M806400200en_AU
dc.identifier.govdoc1319en_AU
dc.identifier.issn0021-9258en_AU
dc.identifier.issue2en_AU
dc.identifier.journaltitleJournal of Biological Chemistryen_AU
dc.identifier.pagination1000-1008en_AU
dc.identifier.urihttp://dx.doi.org/10.1074/jbc.M806400200en_AU
dc.identifier.urihttp://apo.ansto.gov.au/dspace/handle/10238/1850en_AU
dc.identifier.volume284en_AU
dc.language.isoenen_AU
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen_AU
dc.subjectPore structureen_AU
dc.subjectNuclear magnetic resonanceen_AU
dc.subjectInactivationen_AU
dc.subjectActivation analysisen_AU
dc.subjectMolecular dynamics methoden_AU
dc.subjectElectric potentialen_AU
dc.titlePore domain outer helix contributes to both activation and inactivation of the hERG K+ channelen_AU
dc.typeJournal Articleen_AU
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