Identification of the PIP2-binding site on Kir6.2 by molecular modelling and functional analysis

Shozeb Haider, Andrei I. Tarasov, Tim J. Craig, Mark S.P. Sansom, Frances M. Ashcroft

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

ATP-sensitive potassium (KATP) channels couple cell metabolism to electrical activity by regulating K+ fluxes across the plasma membrane. Channel closure is facilitated by ATP, which binds to the pore-forming subunit (Kir6.2). Conversely, channel opening is potentiated by phosphoinositol bisphosphate (PIP2), which binds to Kir6.2 and reduces channel inhibition by ATP. Here, we use homology modelling and ligand docking to identify the PIP2-binding site on Kir6.2. The model is consistent with a large amount of functional data and was further tested by mutagenesis. The fatty acyl tails of PIP2 lie within the membrane and the head group extends downwards to interact with residues in the N terminus (K39, N41, R54), transmembrane domains (K67) and C terminus (R176, R177, E179, R301) of Kir6.2. Our model suggests how PIP2 increases channel opening and decreases ATP binding and channel inhibition. It is likely to be applicable to the PIP2-binding site of other Kir channels, as the residues identified are conserved and influence PIP2 sensitivity in other Kir channel family members.

Original languageEnglish
Pages (from-to)3749-3759
Number of pages11
JournalEMBO Journal
Volume26
Issue number16
DOIs
Publication statusPublished - 22 Aug 2007

Keywords

  • Diabetes
  • Hyperinsulinism
  • K channel
  • Molecular dynamics
  • PIP-binding site

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