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

Astrid Kollewe, Albert Y. Lau, Ashley Sullivan, Benoît Roux, Steve A.N. Goldstein

Research output: Contribution to journalArticle

Abstract

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 K 2PØ, 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.

Original languageEnglish (US)
Pages (from-to)53-68
Number of pages16
JournalJournal of General Physiology
Volume134
Issue number1
DOIs
StatePublished - Jul 1 2009
Externally publishedYes

ASJC Scopus subject areas

  • Physiology

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