A carboxy-terminal inter-helix linker as the site of phosphatidylinositol 4,5-bisphosphate action on Kv7 (M-type) K+ channels

Ciria C. Hernandez, Oleg Zaika, Mark S Shapiro

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

The regulation of M-type (KCNQ [Kv7]) K+ channels by phosphatidylinositol 4,5-bisphosphate (PIP2) has perhaps the best correspondence to physiological signaling, but the site of action and structural motif of PIP2 on these channels have not been established. Using single-channel recordings of chimeras of Kv7.3 and 7.4 channels with highly differential PIP2 sensitivities, we localized a carboxy-terminal inter-helix linker as the primary site of PIP2 action. Point mutants within this linker in Kv7.2 and Kv7.3 identified a conserved cluster of basic residues that interact with the lipid using electrostatic and hydrogen bonds. Homology modeling of this putative PIP2-binding linker in Kv7.2 and Kv7.3 using the solved structure of Kir2.1 and Kir3.1 channels as templates predicts a structure of Kv7.2 and 7.3 very similar to the Kir channels, and to the seven-β-sheet barrel motif common to other PIP2-binding domains. Phosphoinositide-docking simulations predict affinities and interaction energies in accord with the experimental data, and furthermore indicate that the precise identity of residues in the interacting pocket alter channel-PIP2 interactions not only by altering electrostatic energies, but also by allosterically shifting the structure of the lipid-binding surface. The results are likely to shed light on the general structural mechanisms of phosphoinositide regulation of ion channels.

Original languageEnglish (US)
Pages (from-to)361-381
Number of pages21
JournalJournal of General Physiology
Volume132
Issue number3
DOIs
StatePublished - Sep 2008

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Phosphatidylinositols
Static Electricity
Lipids
Ion Channels
Hydrogen

ASJC Scopus subject areas

  • Physiology

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A carboxy-terminal inter-helix linker as the site of phosphatidylinositol 4,5-bisphosphate action on Kv7 (M-type) K+ channels. / Hernandez, Ciria C.; Zaika, Oleg; Shapiro, Mark S.

In: Journal of General Physiology, Vol. 132, No. 3, 09.2008, p. 361-381.

Research output: Contribution to journalArticle

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