Calmodulin acts as a state-dependent switch to control a cardiac potassium channel opening
Open Access
- 30 November 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Advances
- Vol. 6 (50), eabd6798
- https://doi.org/10.1126/sciadv.abd6798
Abstract
Calmodulin (CaM) and phosphatidylinositol 4,5-bisphosphate (PIP2) are potent regulators of the voltage-gated potassium channel KCNQ1 (K(v)7.1), which conducts the cardiac I-Ks 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 PIP 2 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.Funding Information
- National Heart, Lung, and Blood Institute (R01HL126774)
- National Heart, Lung, and Blood Institute (F30HL151042)
- National Institute of Neurological Disorders and Stroke (R01NS092570)
- Science for Life Laboratory
- Göran Gustafssons Foundation
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