TY - JOUR
T1 - Electromechanical coupling of the Kv1.1 voltage-gated K+ channel is fine-tuned by the simplest amino acid residue in the S4-S5 linker
AU - Hasan, Sonia
AU - Megaro, Alfredo
AU - Cenciarini, Marta
AU - Coretti, Lorena
AU - Botti, Fabio Massimo
AU - Imbrici, Paola
AU - Steinbusch, Harry W.M.
AU - Hunter, Therese
AU - Hunter, Gary
AU - Pessia, Mauro
AU - D’Adamo, Maria Cristina
N1 - Publisher Copyright:
© 2020, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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.
AB - 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.
KW - Episodic ataxia type 1
KW - KCNA1
KW - Kv
KW - Kv1.1
KW - S4-S5 linker
KW - Xenopus laevis
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U2 - 10.1007/s00424-020-02414-0
DO - 10.1007/s00424-020-02414-0
M3 - Article
C2 - 32577860
AN - SCOPUS:85086782840
SN - 0031-6768
VL - 472
SP - 899
EP - 909
JO - Pflugers Archiv European Journal of Physiology
JF - Pflugers Archiv European Journal of Physiology
IS - 7
ER -