KCNE1 constrains the voltage sensor of Kv7.1 K+ channels.
Kv7 potassium channels whose mutations cause cardiovascular and neurological disorders are members of the superfamily of voltage-gated K(+) channels, comprising a central pore enclosed by four voltage-sensing domains (VSDs) and sharing a homologous S4 sensor sequence. The Kv7.1 pore-forming subunit can interact with various KCNE auxiliary subunits to form K(+) channels with very different gating behaviors. In an attempt to characterize the nature of the promiscuous gating of Kv7.1 channels, we performed a tryptophan-scanning mutagenesis of the S4 sensor and analyzed the mutation-induced perturbations in gating free energy. Perturbing the gating energetics of Kv7.1 bias most of the mutant channels towards the closed state, while fewer mutations stabilize the open state or the inactivated state. In the absence of auxiliary subunits, mutations of specific S4 residues mimic the gating phenotypes produced by co-assembly of Kv7.1 with either KCNE1 or KCNE3. Many S4 perturbations compromise the ability of KCNE1 to properly regulate Kv7.1 channel gating. The tryptophan-induced packing perturbations and cysteine engineering studies in S4 suggest that KCNE1 lodges at the inter-VSD S4-S1 interface between two adjacent subunits, a strategic location to exert its striking action on Kv7.1 gating functions.
Shamgar
Liora
L
Department of Physiology and Pharmacology, Sackler Medical School, Tel Aviv University, Tel Aviv, Israel.
Haitin
Yoni
Y
Yisharel
Ilanit
I
Malka
Eti
E
Schottelndreier
Hella
H
Peretz
Asher
A
Paas
Yoav
Y
Attali
Bernard
B
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D015640:Ion Channel Gating; D051657:KCNQ1 Potassium Channel / Q000502:physiology*; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D014364:Tryptophan / Q000737:chemistry; D014982:Xenopus laevis
C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D014364:Tryptophan