TY - JOUR
T1 - KCNE1 remodels the voltage sensor of Kv7.1 to modulate channel function
AU - Wu, Dick
AU - Pan, Hua
AU - Delaloye, Kelli
AU - Cui, Jianmin
N1 - Funding Information:
This study was funded by grants from the American Heart Association (Scientist Development Grant 9930025N and Established Investigator Award 0440066N), the United States-Israel Binational Science Foundation (research grant 2001229), and the National Science Foundation of China (grant 30528011 to J.C.). D.W. received a predoctoral fellowship (No. 0910020G) from the American Heart Association. J.C. is the Spencer T. Olin Professor of Biomedical Engineering at Washington University.
PY - 2010/12/1
Y1 - 2010/12/1
N2 - The KCNE1 auxiliary subunit coassembles with the Kv7.1 channel and modulates its properties to generate the cardiac IKs 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 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.
AB - The KCNE1 auxiliary subunit coassembles with the Kv7.1 channel and modulates its properties to generate the cardiac IKs 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 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.
UR - http://www.scopus.com/inward/record.url?scp=78649867712&partnerID=8YFLogxK
U2 - 10.1016/j.bpj.2010.10.018
DO - 10.1016/j.bpj.2010.10.018
M3 - Article
AN - SCOPUS:78649867712
SN - 0006-3495
VL - 99
SP - 3599
EP - 3608
JO - Biophysical Journal
JF - Biophysical Journal
IS - 11
ER -