The Journal of General Physiology
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Published online
doi:10.1085/jgp.200910235
The Journal of General Physiology, Vol. 134, No. 1, 53-68
The Rockefeller University Press, 0022-1295 $30.00
© Kollewe et al.
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ARTICLE

 A structural model for K2P potassium channels based on 23 pairs of interacting sites and continuum electrostatics

Astrid Kollewe1, Albert Y. Lau2, Ashley Sullivan1, Benoît Roux2, and Steve A.N. Goldstein1

1 Institute for Molecular Pediatric Sciences, Department of Pediatrics, and 2 Department of Biochemistry and Molecular Biology, The University of Chicago, Pritzker School of Medicine, Chicago, IL 60637

Correspondence to Steve A.N. Goldstein: sangoldstein{at}uchicago.edu

K2PØ, the two-pore domain potassium background channel that determines cardiac rhythm in Drosophila melanogaster, and its homologues that establish excitable membrane activity in mammals are of unknown structure. K2P subunits have two pore domains flanked by transmembrane (TM) spans: TM1-P1-TM2-TM3-P2-TM4. To establish spatial relationships in K2PØ, we identified pairs of sites that display electrostatic compensation. Channels silenced by the addition of a charge in pore loop 1 (P1) or P2 were restored to function by countercharges at specific second sites. A three-dimensional homology model was determined using the crystal structure of KV1.2, effects of K2PØ mutations to establish alignment, and compensatory charge–charge pairs. The model was refined and validated by continuum electrostatic free energy calculations and covalent linkage of introduced cysteines. K2P channels use two subunits arranged so that the P1 and P2 loops contribute to one pore, identical P loops face each other diagonally across the pore, and the channel complex has bilateral symmetry with a fourfold symmetric selectivity filter.

Abbreviations used in this paper: DTNB, 5,5'-dithiobis(2-nitrobenzoic acid); DTT, dithiothreitol; MD, molecular dynamics; RMSD, root mean square deviation; TM, transmembrane; WT, wild type.

© 2009 Kollewe et al.
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