Cryo-EM Structure of a KCNQ1/CaM Complex Reveals Insights into Congenital Long QT Syndrome.
basic_science · Level V
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- Record sourced from PubMed, PMID 28575668.
- Also identified by DOI 10.1016/j.cell.2017.05.019 and PMC identifier 5562354.
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Abstract
KCNQ1 is the pore-forming subunit of cardiac slow-delayed rectifier potassium (I<sub>Ks</sub>) 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," PIP<sub>2</sub>-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 PIP<sub>2</sub>. 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 PIP<sub>2</sub>, and reveals a regulatory interaction between CaM and KCNQ1 that may explain CaM-mediated LQTS.
Medical subject headings
- Calmodulin
- KCNQ1 Potassium Channel
- Long QT Syndrome