Nature Communications (Feb 2025)

Structural insights into transmembrane helix S0 facilitated RyR1 channel gating by Ca2+/ATP

  • Risheng Wei,
  • Qiang Chen,
  • Lei Zhang,
  • Congcong Liu,
  • Chuang Liu,
  • Chang-Cheng Yin,
  • Hongli Hu

DOI
https://doi.org/10.1038/s41467-025-57074-4
Journal volume & issue
Vol. 16, no. 1
pp. 1 – 10

Abstract

Read online

Abstract The type-1 ryanodine receptor (RyR1) is an intracellular calcium release channel for skeletal muscle excitation-contraction coupling. Previous structural studies showed that the RyR1 activity is modulated by the exogenous regulators including caffeine, ryanodine, PCB-95 and diamide. An additional transmembrane helix, located adjacent to S1 and S4, has been observed in some structures, although its function remains unclear. Here, we report that using a mild purification procedure, this helix is co-purified with RyR1 and is designated as S0. When RyR1 is coupled with S0, it can be activated by Ca2+ to an open state; however when decoupled from S0, it remains in primed state. S0 regulates the channel conformation by directly affecting the TM domain via the pVSD-S0-S4/S5 linker coupling, which facilitates the dilation of S6. Our results demonstrate that S0 is an essential component of RyR1 and plays a key role in the physiological regulation of RyR1 channel gating.