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Upgraded molecular models of the human KCNQ1 potassium channel

Author

Listed:
  • Georg Kuenze
  • Amanda M Duran
  • Hope Woods
  • Kathryn R Brewer
  • Eli Fritz McDonald
  • Carlos G Vanoye
  • Alfred L George Jr.
  • Charles R Sanders
  • Jens Meiler

Abstract

The voltage-gated potassium channel KCNQ1 (KV7.1) assembles with the KCNE1 accessory protein to generate the slow delayed rectifier current, IKS, which is critical for membrane repolarization as part of the cardiac action potential. Loss-of-function (LOF) mutations in KCNQ1 are the most common cause of congenital long QT syndrome (LQTS), type 1 LQTS, an inherited genetic predisposition to cardiac arrhythmia and sudden cardiac death. A detailed structural understanding of KCNQ1 is needed to elucidate the molecular basis for KCNQ1 LOF in disease and to enable structure-guided design of new anti-arrhythmic drugs. In this work, advanced structural models of human KCNQ1 in the resting/closed and activated/open states were developed by Rosetta homology modeling guided by newly available experimentally-based templates: X. leavis KCNQ1 and various resting voltage sensor structures. Using molecular dynamics (MD) simulations, the capacity of the models to describe experimentally established channel properties including state-dependent voltage sensor gating charge interactions and pore conformations, PIP2 binding sites, and voltage sensor–pore domain interactions were validated. Rosetta energy calculations were applied to assess the utility of each model in interpreting mutation-evoked KCNQ1 dysfunction by predicting the change in protein thermodynamic stability for 50 experimentally characterized KCNQ1 variants with mutations located in the voltage-sensing domain. Energetic destabilization was successfully predicted for folding-defective KCNQ1 LOF mutants whereas wild type-like mutants exhibited no significant energetic frustrations, which supports growing evidence that mutation-induced protein destabilization is an especially common cause of KCNQ1 dysfunction. The new KCNQ1 Rosetta models provide helpful tools in the study of the structural basis for KCNQ1 function and can be used to generate hypotheses to explain KCNQ1 dysfunction.

Suggested Citation

  • Georg Kuenze & Amanda M Duran & Hope Woods & Kathryn R Brewer & Eli Fritz McDonald & Carlos G Vanoye & Alfred L George Jr. & Charles R Sanders & Jens Meiler, 2019. "Upgraded molecular models of the human KCNQ1 potassium channel," PLOS ONE, Public Library of Science, vol. 14(9), pages 1-33, September.
  • Handle: RePEc:plo:pone00:0220415
    DOI: 10.1371/journal.pone.0220415
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    References listed on IDEAS

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    1. Zhe Lu & Angela M. Klem & Yajamana Ramu, 2001. "Ion conduction pore is conserved among potassium channels," Nature, Nature, vol. 413(6858), pages 809-813, October.
    2. Daniel Schmidt & Qiu-Xing Jiang & Roderick MacKinnon, 2006. "Phospholipids and the origin of cationic gating charges in voltage sensors," Nature, Nature, vol. 444(7120), pages 775-779, December.
    3. Koichi Nakajo & Yoshihiro Kubo, 2014. "Steric hindrance between S4 and S5 of the KCNQ1/KCNE1 channel hampers pore opening," Nature Communications, Nature, vol. 5(1), pages 1-11, September.
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