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Structural basis for hyperpolarization-dependent opening of human HCN1 channel

Author

Listed:
  • Verena Burtscher

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Jonathan Mount

    (Washington University School of Medicine
    Washington University School of Medicine
    Icahn School of Medicine at Mount Sinai)

  • Jian Huang

    (University of Massachusetts)

  • John Cowgill

    (Washington University School of Medicine
    Washington University School of Medicine
    KTH Royal Institute of Technology)

  • Yongchang Chang

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Kathleen Bickel

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Jianhan Chen

    (University of Massachusetts)

  • Peng Yuan

    (Washington University School of Medicine
    Washington University School of Medicine
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Baron Chanda

    (Washington University School of Medicine
    Washington University School of Medicine
    Washington University School of Medicine
    Washington University School of Medicine)

Abstract

Hyperpolarization and cyclic nucleotide (HCN) activated ion channels are critical for the automaticity of action potentials in pacemaking and rhythmic electrical circuits in the human body. Unlike most voltage-gated ion channels, the HCN and related plant ion channels activate upon membrane hyperpolarization. Although functional studies have identified residues in the interface between the voltage-sensing and pore domain as crucial for inverted electromechanical coupling, the structural mechanisms for this unusual voltage-dependence remain unclear. Here, we present cryo-electron microscopy structures of human HCN1 corresponding to Closed, Open, and a putative Intermediate state. Our structures reveal that the downward motion of the gating charges past the charge transfer center is accompanied by concomitant unwinding of the inner end of the S4 and S5 helices, disrupting the tight gating interface observed in the Closed state structure. This helix-coil transition at the intracellular gating interface accompanies a concerted iris-like dilation of the pore helices and underlies the reversed voltage dependence of HCN channels.

Suggested Citation

  • Verena Burtscher & Jonathan Mount & Jian Huang & John Cowgill & Yongchang Chang & Kathleen Bickel & Jianhan Chen & Peng Yuan & Baron Chanda, 2024. "Structural basis for hyperpolarization-dependent opening of human HCN1 channel," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49599-x
    DOI: 10.1038/s41467-024-49599-x
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    References listed on IDEAS

    as
    1. Minghui Li & Xiaoyuan Zhou & Shu Wang & Ioannis Michailidis & Ye Gong & Deyuan Su & Huan Li & Xueming Li & Jian Yang, 2017. "Structure of a eukaryotic cyclic-nucleotide-gated channel," Nature, Nature, vol. 542(7639), pages 60-65, February.
    2. Brian J. Wainger & Matthew DeGennaro & Bina Santoro & Steven A. Siegelbaum & Gareth R. Tibbs, 2001. "Molecular mechanism of cAMP modulation of HCN pacemaker channels," Nature, Nature, vol. 411(6839), pages 805-810, June.
    3. David S. White & Sandipan Chowdhury & Vinay Idikuda & Ruohan Zhang & Scott T. Retterer & Randall H. Goldsmith & Baron Chanda, 2021. "cAMP binding to closed pacemaker ion channels is non-cooperative," Nature, Nature, vol. 595(7868), pages 606-610, July.
    4. Andreas Ludwig & Xiangang Zong & Michael Jeglitsch & Franz Hofmann & Martin Biel, 1998. "A family of hyperpolarization-activated mammalian cation channels," Nature, Nature, vol. 393(6685), pages 587-591, June.
    5. Michael David Clark & Gustavo F. Contreras & Rong Shen & Eduardo Perozo, 2020. "Electromechanical coupling in the hyperpolarization-activated K+ channel KAT1," Nature, Nature, vol. 583(7814), pages 145-149, July.
    6. Julia Kowal & Mohamed Chami & Paul Baumgartner & Marcel Arheit & Po-Lin Chiu & Martina Rangl & Simon Scheuring & Gunnar F. Schröder & Crina M. Nimigean & Henning Stahlberg, 2014. "Ligand-induced structural changes in the cyclic nucleotide-modulated potassium channel MloK1," Nature Communications, Nature, vol. 5(1), pages 1-10, May.
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