Cryo-EM Structure of a KCNQ1/CaM Complex Reveals Insights into Congenital Long QT Syndrome

Cell. 2017 Jun 1;169(6):1042-1050.e9. doi: 10.1016/j.cell.2017.05.019.


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.

Keywords: CaM; KCNQ1; PIP2; cryo-EM; ion channel structure; long QT syndrome.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calmodulin / chemistry*
  • Calmodulin / metabolism
  • Cryoelectron Microscopy
  • Humans
  • KCNQ1 Potassium Channel / chemistry*
  • KCNQ1 Potassium Channel / genetics
  • KCNQ1 Potassium Channel / metabolism
  • Long QT Syndrome / metabolism*
  • Models, Molecular
  • Mutation
  • Sequence Alignment
  • Xenopus laevis


  • Calmodulin
  • KCNQ1 Potassium Channel