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

Johanna L. Syrjänen, Max Epstein, Ricardo Gómez and Hiro Furukawa ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39388-3

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