KCNE1 remodels the voltage sensor of Kv7.1 to modulate channel function.
The KCNE1 auxiliary subunit coassembles with the Kv7.1 channel and modulates its properties to generate the cardiac I(Ks) current. Recent biophysical evidence suggests that KCNE1 interacts with the voltage-sensing domain (VSD) of Kv7.1. To investigate the mechanism of how KCNE1 affects the VSD to alter the voltage dependence of channel activation, we perturbed the VSD of Kv7.1 by mutagenesis and chemical modification in the absence and presence of KCNE1. Mutagenesis of S4 in Kv7.1 indicates that basic residues in the N-terminal half (S4-N) and C-terminal half (S4-C) of S4 are important for stabilizing the resting and activated states of the channel, respectively. KCNE1 disrupts electrostatic interactions involving S4-C, specifically with the lower conserved glutamate in S2 (Glu(170) or E2). Likewise, Trp scanning of S4 shows that mutations to a cluster of residues in S4-C eliminate current in the presence of KCNE1. In addition, KCNE1 affects S4-N by enhancing MTS accessibility to the top of the VSD. Consistent with the structure of Kv channels and previous studies on the KCNE1-Kv7.1 interaction, these results suggest that KCNE1 alters the interactions of S4 residues with the surrounding protein environment, possibly by changing the protein packing around S4, thereby affecting the voltage dependence of Kv7.1.
Department of Biomedical Engineering, and Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, Missouri, USA.
Dick
D
Wu
Hua
H
Pan
Kelli
K
Delaloye
Jianmin
J
Cui
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D005110:Extracellular Space / Q000378:metabolism; D015640:Ion Channel Gating; D051657:KCNQ1 Potassium Channel / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D014982:Xenopus laevis
D000596:Amino Acids; D051657:KCNQ1 Potassium Channel; D024642:Potassium Channels, Voltage-Gated