title: Interactions between the N-terminal tail and the gating machinery of hERG K⁺ channels both in closed and open/inactive states.
abstract: The N-terminal-most N-tail of the human ether-à-go-go-related gene (hERG) potassium channel is a crucial modulator of deactivation through its interactions with the S4-S5 loop and/or the C-linker/cNBD, leading to a stabilization of the channel's open state. Not only the N-terminal, but also the initial C-terminal region of the channel can modulate the transitions between the open and closed states either by direct or by indirect/allosteric interactions with the gating machinery. However, while a physical proximity of the N-tail to the gating machinery has been demonstrated in the closed state, data about their possible interaction in other channel conformations have been lacking. Using a site-directed cysteine mutagenesis and disulfide chemistry approach, we present here evidence that a physical proximity between the N-tail and the gating-related structures can also exist in channels held between pulses in the open/inactive state, highlighting the physiological and functional relevance of the direct interactions between the N-terminal tail and the S4-S5 loop and/or C-linker structures for modulation of channel.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Oviedo, 33006, Oviedo, Spain, pdelapena@uniovi.es.
authors.forename: Pilar
authors.initials: P
authors.lastname: de la Peña
authors.forename: Angeles
authors.initials: A
authors.lastname: Machín
authors.forename: Jorge
authors.initials: J
authors.lastname: Fernández-Trillo
authors.forename: Pedro
authors.initials: P
authors.lastname: Domínguez
authors.forename: Francisco
authors.initials: F
authors.lastname: Barros
mesh_terms: D000818:Animals; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating; D008564:Membrane Potentials; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009865:Oocytes; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013997:Time Factors; D014982:Xenopus laevis
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human