Tyrosine Residues from the S4-S5 Linker of Kv11.1 Channels Are Critical for Slow Deactivation.
Slow deactivation of Kv11.1 channels is critical for its function in the heart. The S4-S5 linker, which joins the voltage sensor and pore domains, plays a critical role in this slow deactivation gating. Here, we use NMR spectroscopy to identify the membrane-bound surface of the S4S5 linker, and we show that two highly conserved tyrosine residues within the KCNH subfamily of channels are membrane-associated. Site-directed mutagenesis and electrophysiological analysis indicates that Tyr-542 interacts with both the pore domain and voltage sensor residues to stabilize activated conformations of the channel, whereas Tyr-545 contributes to the slow kinetics of deactivation by primarily stabilizing the transition state between the activated and closed states. Thus, the two tyrosine residues in the Kv11.1 S4S5 linker play critical but distinct roles in the slow deactivation phenotype, which is a hallmark of Kv11.1 channels.
From the Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst and the St. Vincent's Clinical School, University of New South Wales, Victoria Street, Darlinghurst, New South Wales 2010, Australia and.
Chai-Ann
0000-0002-3120-5450
CA
Ng
the Department of Chemistry, Université du Québec à Montréal, Montreal H3C 3P8, Québec, Canada.
Andrée E
AE
Gravel
From the Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst and the St. Vincent's Clinical School, University of New South Wales, Victoria Street, Darlinghurst, New South Wales 2010, Australia and.
Matthew D
MD
Perry
the Department of Chemistry, Université du Québec à Montréal, Montreal H3C 3P8, Québec, Canada.
Alexandre A
AA
Arnold
the Department of Chemistry, Université du Québec à Montréal, Montreal H3C 3P8, Québec, Canada marcotte.isabelle@uqam.ca.
Isabelle
I
Marcotte
From the Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst and the St. Vincent's Clinical School, University of New South Wales, Victoria Street, Darlinghurst, New South Wales 2010, Australia and j.vandenberg@victorchang.edu.au.
Jamie I
0000-0002-3859-3716
JI
Vandenberg
D000818:Animals; D002462:Cell Membrane / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000072237:ERG1 Potassium Channel / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014981:Xenopus
D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human; D010455:Peptides
Kv11.1; S4S5 linker; electrophysiology; gating; hERG; ion channel; lipid membrane; nuclear magnetic resonance (NMR); potassium channel; site-directed mutagenesis