TY - JOUR
T1 - PIP2-dependent coupling is prominent in Kv7.1 due to weakened interactions between S4-S5 and S6
AU - Kasimova, Marina A.
AU - Zaydman, Mark A.
AU - Cui, Jianmin
AU - Tarek, Mounir
N1 - Funding Information:
We thank Dr. Y. Okamura (Osaka University, Osaka, Japan) for the CiVSP clone, Dr. S. Goldstein (Brandeis University, MA) for the KCNQ1 clone, and Dr. D. McKinnon (SUNY, Stony Brook, NY) for the rat KCNQ2 and KCNQ3 clones. We acknowledge PRACE for awarding us access to resource CURIE based in FRANCE at the TGCC and SUPERMUC based in Germany at the LRZ. MK acknowledges MSU Supercomputer Lomonosov. This work was supported by NIH Grants R01-HL70393 and R01-NS060706, National Science Foundation of China Grant 31271143 and 81120108004 to JC, American Heart Association predoctoral fellowship 11PRE5720009 to MAZ, and French Government Scholarship for joint PhD 780584E to MAK. JC is the Professor of Biomedical Engineering on the Spencer T. Olin Endowment.
PY - 2015/1/6
Y1 - 2015/1/6
N2 - Among critical aspects of voltage-gated potassium (Kv) channels' functioning is the effective communication between their two composing domains, the voltage sensor (VSD) and the pore. This communication, called coupling, might be transmitted directly through interactions between these domains and, as recently proposed, indirectly through interactions with phosphatidylinositol-4,5-bisphosphate (PIP2), a minor lipid of the inner plasma membrane leaflet. Here, we show how the two components of coupling, mediated by protein-protein or protein-lipid interactions, both contribute in the Kv7.1 functioning. On the one hand, using molecular dynamics simulations, we identified a Kv7.1 PIP2 binding site that involves residues playing a key role in PIP2-dependent coupling. On the other hand, combined theoretical and experimental approaches have shown that the direct interaction between the segments of the VSD (S4-S5) and the pore (S6) is weakened by electrostatic repulsion. Finally, we conclude that due to weakened protein-protein interactions, the PIP2-dependent coupling is especially prominent in Kv7.1.
AB - Among critical aspects of voltage-gated potassium (Kv) channels' functioning is the effective communication between their two composing domains, the voltage sensor (VSD) and the pore. This communication, called coupling, might be transmitted directly through interactions between these domains and, as recently proposed, indirectly through interactions with phosphatidylinositol-4,5-bisphosphate (PIP2), a minor lipid of the inner plasma membrane leaflet. Here, we show how the two components of coupling, mediated by protein-protein or protein-lipid interactions, both contribute in the Kv7.1 functioning. On the one hand, using molecular dynamics simulations, we identified a Kv7.1 PIP2 binding site that involves residues playing a key role in PIP2-dependent coupling. On the other hand, combined theoretical and experimental approaches have shown that the direct interaction between the segments of the VSD (S4-S5) and the pore (S6) is weakened by electrostatic repulsion. Finally, we conclude that due to weakened protein-protein interactions, the PIP2-dependent coupling is especially prominent in Kv7.1.
UR - http://www.scopus.com/inward/record.url?scp=84945219998&partnerID=8YFLogxK
U2 - 10.1038/srep07474
DO - 10.1038/srep07474
M3 - Article
C2 - 25559286
AN - SCOPUS:84945219998
SN - 2045-2322
VL - 5
JO - Scientific reports
JF - Scientific reports
M1 - 7474
ER -