TY - JOUR
T1 - Calmodulin acts as a state-dependent switch to control a cardiac potassium channel opening
AU - Kang, Po Wei
AU - Westerlund, Annie M.
AU - Shi, Jingyi
AU - White, Kelli Mc Farland
AU - Dou, Alex K.
AU - Cui, Amy H.
AU - Silva, Jonathan R.
AU - Delemotte, Lucie
AU - Cui, Jianmin
N1 - Funding Information:
This work was supported by grants from NIH R01HL126774 (J.C.), R01NS092570 (J.R.S.), F30HL151042 (P.W.K.), grants from the Science for Life Laboratory, and the Göran Gustafsson Foundation (L.D.). The simulations were performed on resources provided by the Swedish National Infrastructure for Computing (SNIC) at the PDC Centre for High Performance Computing (PDC-HPC).
Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved;
PY - 2020/12/11
Y1 - 2020/12/11
N2 - Calmodulin (CaM) and phosphatidylinositol 4,5-bisphosphate (PIP2) are potent regulators of the voltage-gated potassium channel KCNQ1 (KV7.1), which conducts the cardiac IKs current. Although cryo–electron microscopy structures revealed intricate interactions between the KCNQ1 voltage-sensing domain (VSD), CaM, and PIP2, the functional consequences of these interactions remain unknown. Here, we show that CaM-VSD interactions act as a state-dependent switch to control KCNQ1 pore opening. Combined electrophysiology and molecular dynamics network analysis suggest that VSD transition into the fully activated state allows PIP2 to compete with CaM for binding to VSD. This leads to conformational changes that alter VSD-pore coupling to stabilize open states. We identify a motif in the KCNQ1 cytosolic domain, which works downstream of CaM-VSD interactions to facilitate the conformational change. Our findings suggest a gating mechanism that integrates PIP2 and CaM in KCNQ1 voltage-dependent activation, yielding insights into how KCNQ1 gains the phenotypes critical for its physiological function.
AB - Calmodulin (CaM) and phosphatidylinositol 4,5-bisphosphate (PIP2) are potent regulators of the voltage-gated potassium channel KCNQ1 (KV7.1), which conducts the cardiac IKs current. Although cryo–electron microscopy structures revealed intricate interactions between the KCNQ1 voltage-sensing domain (VSD), CaM, and PIP2, the functional consequences of these interactions remain unknown. Here, we show that CaM-VSD interactions act as a state-dependent switch to control KCNQ1 pore opening. Combined electrophysiology and molecular dynamics network analysis suggest that VSD transition into the fully activated state allows PIP2 to compete with CaM for binding to VSD. This leads to conformational changes that alter VSD-pore coupling to stabilize open states. We identify a motif in the KCNQ1 cytosolic domain, which works downstream of CaM-VSD interactions to facilitate the conformational change. Our findings suggest a gating mechanism that integrates PIP2 and CaM in KCNQ1 voltage-dependent activation, yielding insights into how KCNQ1 gains the phenotypes critical for its physiological function.
UR - http://www.scopus.com/inward/record.url?scp=85097930569&partnerID=8YFLogxK
U2 - 10.1126/sciadv.abd6798
DO - 10.1126/sciadv.abd6798
M3 - Article
C2 - 33310856
AN - SCOPUS:85097930569
SN - 2375-2548
VL - 6
JO - Science Advances
JF - Science Advances
IS - 50
M1 - eabd6798
ER -