Molecular coupling in the human ether-a-go-go-related gene-1 (hERG1) K + channel inactivation pathway

Tania Ferrer, Julio Cordero-Morales, Marcelo Arias, Eckhard Ficker, David Medovoy, Eduardo Perozo, Martin Tristani-Firouzi

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Emerging evidence suggests that K + channel inactivation involves coupling between residues in adjacent regions of the channel. Human ether-a-go-go-related gene-1 (hERG1) K +channels undergo a fast inactivation gating process that is crucial for maintaining electrical stability in the heart. The molecular mechanisms that drive inactivation in hERG1 channels are unknown. Using alanine scanning mutagenesis, we show that a pore helix residue (Thr-618) that points toward the S5 segment is critical for normal inactivation gating. Amino acid substitutions at position 618 modulate the free energy of inactivation gating, causing enhanced or reduced inactivation. Mutation of an S5 residue that is predicted to be adjacent to Thr-618 (W568L) abolishes inactivation and alters ion selectivity. The introduction of the Thr-618-equivalent residue in Kv1.5 enhances inactivation. Molecular dynamic simulations of the Kv1.2 tetramer reveal van der Waals coupling between hERG1 618- and 568-equivalent residues and a significant increase in interaction energies when threonine is introduced at the 618-equivalent position. We propose that coupling between the S5 segment and pore helix may participate in the inactivation process in hERG1 channels.

Original languageEnglish (US)
Pages (from-to)39091-39099
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number45
DOIs
StatePublished - Nov 11 2011

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Ether
Genes
Mutagenesis
Threonine
Amino Acid Substitution
Molecular Dynamics Simulation
Alanine
Free energy
Molecular dynamics
Substitution reactions
Ions
Scanning
Amino Acids
Mutation
Computer simulation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Molecular coupling in the human ether-a-go-go-related gene-1 (hERG1) K + channel inactivation pathway. / Ferrer, Tania; Cordero-Morales, Julio; Arias, Marcelo; Ficker, Eckhard; Medovoy, David; Perozo, Eduardo; Tristani-Firouzi, Martin.

In: Journal of Biological Chemistry, Vol. 286, No. 45, 11.11.2011, p. 39091-39099.

Research output: Contribution to journalArticle

Ferrer, Tania ; Cordero-Morales, Julio ; Arias, Marcelo ; Ficker, Eckhard ; Medovoy, David ; Perozo, Eduardo ; Tristani-Firouzi, Martin. / Molecular coupling in the human ether-a-go-go-related gene-1 (hERG1) K + channel inactivation pathway. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 45. pp. 39091-39099.
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