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XB-ART-53850
Cell 2017 Jun 01;1696:1042-1050.e9. doi: 10.1016/j.cell.2017.05.019.
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Cryo-EM Structure of a KCNQ1/CaM Complex Reveals Insights into Congenital Long QT Syndrome.

Sun J , MacKinnon R .


Abstract
KCNQ1 is the pore-forming subunit of cardiac slow-delayed rectifier potassium (IKs) channels. Mutations in the kcnq1 gene are the leading cause of congenital long QT syndrome (LQTS). Here, we present the cryoelectron microscopy (cryo-EM) structure of a KCNQ1/calmodulin (CaM) complex. The conformation corresponds to an "uncoupled," PIP2-free state of KCNQ1, with activated voltage sensors and a closed pore. Unique structural features within the S4-S5 linker permit uncoupling of the voltage sensor from the pore in the absence of PIP2. CaM contacts the KCNQ1 voltage sensor through a specific interface involving a residue on CaM that is mutated in a form of inherited LQTS. Using an electrophysiological assay, we find that this mutation on CaM shifts the KCNQ1 voltage-activation curve. This study describes one physiological form of KCNQ1, depolarized voltage sensors with a closed pore in the absence of PIP2, and reveals a regulatory interaction between CaM and KCNQ1 that may explain CaM-mediated LQTS.

PubMed ID: 28575668
PMC ID: PMC5562354
Article link: Cell
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: kcnq1

References [+] :
Adams, PHENIX: a comprehensive Python-based system for macromolecular structure solution. 2010, Pubmed