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Structure of human CALHM1 reveals key locations for channel regulation and blockade by ruthenium red

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  • Johanna L. Syrjänen

    (Cold Spring Harbor Laboratory, Cold Spring Harbor)

  • Max Epstein

    (Cold Spring Harbor Laboratory, Cold Spring Harbor)

  • Ricardo Gómez

    (Cold Spring Harbor Laboratory, Cold Spring Harbor)

  • Hiro Furukawa

    (Cold Spring Harbor Laboratory, Cold Spring Harbor)

Abstract

Calcium homeostasis modulator 1 (CALHM1) is a voltage-dependent channel involved in neuromodulation and gustatory signaling. Despite recent progress in the structural biology of CALHM1, insights into functional regulation, pore architecture, and channel blockade remain limited. Here we present the cryo-EM structure of human CALHM1, revealing an octameric assembly pattern similar to the non-mammalian CALHM1s and the lipid-binding pocket conserved across species. We demonstrate by MD simulations that this pocket preferentially binds a phospholipid over cholesterol to stabilize its structure and regulate the channel activities. Finally, we show that residues in the amino-terminal helix form the channel pore that ruthenium red binds and blocks.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39388-3
    DOI: 10.1038/s41467-023-39388-3
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    References listed on IDEAS

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    2. 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.
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    4. 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.
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    1. Nazia Hussain & Ashish Apotikar & Shabareesh Pidathala & Sourajit Mukherjee & Ananth Prasad Burada & Sujit Kumar Sikdar & Kutti R. Vinothkumar & Aravind Penmatsa, 2024. "Cryo-EM structures of pannexin 1 and 3 reveal differences among pannexin isoforms," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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