Electromechanical coupling of the Kv1.1 voltage-gated K+ channel is fine-tuned by the simplest amino acid residue in the S4-S5 linker

Sonia Hasan, Alfredo Megaro, Marta Cenciarini, Lorena Coretti, Fabio Massimo Botti, Paola Imbrici, Harry W.M. Steinbusch, Therese Hunter, Gary Hunter, Mauro Pessia, Maria Cristina D’Adamo

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Investigating the Shaker-related K+ channel Kv1.1, the dysfunction of which is responsible for episodic ataxia 1 (EA1), at the functional and molecular level provides valuable understandings on normal channel dynamics, structural correlates underlying voltage-gating, and disease-causing mechanisms. Most studies focused on apparently functional amino acid residues composing voltage-gated K+ channels, neglecting the simplest ones. Glycine at position 311 of Kv1.1 is highly conserved both evolutionarily and within the Kv channel superfamily, is located in a region functionally relevant (the S4-S5 linker), and results in overt disease when mutated (p.G311D). By mutating the G311 residue to aspartate, we show here that the channel voltage-gating, activation, deactivation, inactivation, and window currents are markedly affected. In silico, modeling shows this glycine residue is strategically placed at one end of the linker helix which must be free to both bend and move past other portions of the protein during the channel’s opening and closing. This is befitting of a glycine residue as its small neutral side chain allows for movement unhindered by interaction with any other amino acid. Results presented reveal the crucial importance of a distinct glycine residue, within the S4-S5 linker, in the voltage-dependent electromechanical coupling that control channel gating.

Original languageEnglish
Pages (from-to)899-909
Number of pages11
JournalPflugers Archiv European Journal of Physiology
Volume472
Issue number7
DOIs
Publication statusPublished - Jul 1 2020

Keywords

  • Episodic ataxia type 1
  • KCNA1
  • Kv
  • Kv1.1
  • S4-S5 linker
  • Xenopus laevis

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

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