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The structures and gating mechanism of human calcium homeostasis modulator 2

Author

Listed:
  • Wooyoung Choi

    (Van Andel Institute)

  • Nicolina Clemente

    (Van Andel Institute)

  • Weinan Sun

    (Oregon Health & Science University
    Janelia Research Campus)

  • Juan Du

    (Van Andel Institute)

  • Wei Lü

    (Van Andel Institute)

Abstract

Calcium homeostasis modulators (CALHMs) are voltage-gated, Ca2+-inhibited nonselective ion channels that act as major ATP release channels, and have important roles in gustatory signalling and neuronal toxicity1–3. Dysfunction of CALHMs has previously been linked to neurological disorders1. Here we present cryo-electron microscopy structures of the human CALHM2 channel in the Ca2+-free active or open state and in the ruthenium red (RUR)-bound inhibited state, at resolutions up to 2.7 Å. Our work shows that purified CALHM2 channels form both gap junctions and undecameric hemichannels. The protomer shows a mirrored arrangement of the transmembrane domains (helices S1–S4) relative to other channels with a similar topology, such as connexins, innexins and volume-regulated anion channels4–8. Upon binding to RUR, we observed a contracted pore with notable conformational changes of the pore-lining helix S1, which swings nearly 60° towards the pore axis from a vertical to a lifted position. We propose a two-section gating mechanism in which the S1 helix coarsely adjusts, and the N-terminal helix fine-tunes, the pore size. We identified a RUR-binding site near helix S1 that may stabilize this helix in the lifted conformation, giving rise to channel inhibition. Our work elaborates on the principles of CALHM2 channel architecture and symmetry, and the mechanism that underlies channel inhibition.

Suggested Citation

  • Wooyoung Choi & Nicolina Clemente & Weinan Sun & Juan Du & Wei Lü, 2019. "The structures and gating mechanism of human calcium homeostasis modulator 2," Nature, Nature, vol. 576(7785), pages 163-167, December.
  • Handle: RePEc:nat:nature:v:576:y:2019:i:7785:d:10.1038_s41586-019-1781-3
    DOI: 10.1038/s41586-019-1781-3
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    Citations

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    Cited by:

    1. Arthur Neuberger & Kirill D. Nadezhdin & Alexander I. Sobolevsky, 2021. "Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    2. Johanna L. Syrjänen & Max Epstein & Ricardo Gómez & Hiro Furukawa, 2023. "Structure of human CALHM1 reveals key locations for channel regulation and blockade by ruthenium red," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Zhihui He & Yonghui Zhao & Michael J. Rau & James A. J. Fitzpatrick & Rajan Sah & Hongzhen Hu & Peng Yuan, 2023. "Structural and functional analysis of human pannexin 2 channel," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    4. Hang Zhang & Shiyu Wang & Zhenzhen Zhang & Mengzhuo Hou & Chunyu Du & Zhenye Zhao & Horst Vogel & Zhifang Li & Kaige Yan & Xiaokang Zhang & Jianping Lu & Yujie Liang & Shuguang Yuan & Daping Wang & Hu, 2023. "Cryo-EM structure of human heptameric pannexin 2 channel," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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