Structural basis of slow activation gating in the cardiac IKs channel complex
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Structural basis of slow activation gating in the cardiac IKs channel complex. / Strutz-Seebohm, Nathalie; Pusch, Michael; Wolf, Steffen; Stoll, Raphael; Tapken, Daniel; Gerwert, Klaus; Attali, Bernard; Seebohm, Guiscard.
In: Cellular Physiology and Biochemistry, Vol. 27, No. 5, 2011, p. 443-452.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Structural basis of slow activation gating in the cardiac IKs channel complex
AU - Strutz-Seebohm, Nathalie
AU - Pusch, Michael
AU - Wolf, Steffen
AU - Stoll, Raphael
AU - Tapken, Daniel
AU - Gerwert, Klaus
AU - Attali, Bernard
AU - Seebohm, Guiscard
N1 - Key Words: KCNQ1/KCNE1, structure, model
PY - 2011
Y1 - 2011
N2 - Accessory ß-subunits of the KCNE gene family modulate the function of various cation channel a-subunits by the formation of heteromultimers. Among the most dramatic changes of biophysical properties of a voltage-gated channel by KCNEs are the effects of KCNE1 on KCNQ1 channels. KCNQ1 and KCNE1 are believed to form nativeI(Ks) channels. Here, we characterize molecular determinants of KCNE1 interaction with KCNQ1 channels by scanning mutagenesis, double mutant cycle analysis, and molecular dynamics simulations. Our findings suggest that KCNE1 binds to the outer face of the KCNQ1 channel pore domain, modifies interactions between voltage sensor, S4-S5 linker and the pore domain, leading to structural modifications of the selectivity filter and voltage sensor domain. Molecular dynamics simulations suggest a stable interaction of the KCNE1 transmembrane a-helix with the pore domain S5/S6 and part of the voltage sensor domain S4 of KCNQ1 in a putative pre-open channel state. Formation of this state may induce slow activation gating, the pivotal characteristic of native cardiac I(Ks) channels. This new KCNQ1-KCNE1 model may become useful for dynamic modeling of disease-associated mutant I(Ks) channels.
AB - Accessory ß-subunits of the KCNE gene family modulate the function of various cation channel a-subunits by the formation of heteromultimers. Among the most dramatic changes of biophysical properties of a voltage-gated channel by KCNEs are the effects of KCNE1 on KCNQ1 channels. KCNQ1 and KCNE1 are believed to form nativeI(Ks) channels. Here, we characterize molecular determinants of KCNE1 interaction with KCNQ1 channels by scanning mutagenesis, double mutant cycle analysis, and molecular dynamics simulations. Our findings suggest that KCNE1 binds to the outer face of the KCNQ1 channel pore domain, modifies interactions between voltage sensor, S4-S5 linker and the pore domain, leading to structural modifications of the selectivity filter and voltage sensor domain. Molecular dynamics simulations suggest a stable interaction of the KCNE1 transmembrane a-helix with the pore domain S5/S6 and part of the voltage sensor domain S4 of KCNQ1 in a putative pre-open channel state. Formation of this state may induce slow activation gating, the pivotal characteristic of native cardiac I(Ks) channels. This new KCNQ1-KCNE1 model may become useful for dynamic modeling of disease-associated mutant I(Ks) channels.
KW - Former Faculty of Pharmaceutical Sciences
U2 - 10.1159/000329965
DO - 10.1159/000329965
M3 - Journal article
C2 - 21691061
VL - 27
SP - 443
EP - 452
JO - Cellular Physiology and Biochemistry
JF - Cellular Physiology and Biochemistry
SN - 1015-8987
IS - 5
ER -
ID: 38384443