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Structural basis for activation and gating of IP3 receptors

Author

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  • Emily A. Schmitz

    (Vanderbilt University, School of Medicine
    Vanderbilt University)

  • Hirohide Takahashi

    (Vanderbilt University, School of Medicine
    Vanderbilt University)

  • Erkan Karakas

    (Vanderbilt University, School of Medicine
    Vanderbilt University)

Abstract

A pivotal component of the calcium (Ca2+) signaling toolbox in cells is the inositol 1,4,5-triphosphate (IP3) receptor (IP3R), which mediates Ca2+ release from the endoplasmic reticulum (ER), controlling cytoplasmic and organellar Ca2+ concentrations. IP3Rs are co-activated by IP3 and Ca2+, inhibited by Ca2+ at high concentrations, and potentiated by ATP. However, the underlying molecular mechanisms are unclear. Here we report cryo-electron microscopy (cryo-EM) structures of human type-3 IP3R obtained from a single dataset in multiple gating conformations: IP3-ATP bound pre-active states with closed channels, IP3-ATP-Ca2+ bound active state with an open channel, and IP3-ATP-Ca2+ bound inactive state with a closed channel. The structures demonstrate how IP3-induced conformational changes prime the receptor for activation by Ca2+, how Ca2+ binding leads to channel opening, and how ATP modulates the activity, providing insights into the long-sought questions regarding the molecular mechanism underpinning receptor activation and gating.

Suggested Citation

  • Emily A. Schmitz & Hirohide Takahashi & Erkan Karakas, 2022. "Structural basis for activation and gating of IP3 receptors," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29073-2
    DOI: 10.1038/s41467-022-29073-2
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    Cited by:

    1. Navid Paknejad & Vinay Sapuru & Richard K. Hite, 2023. "Structural titration reveals Ca2+-dependent conformational landscape of the IP3 receptor," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Guizhen Fan & Mariah R. Baker & Lara E. Terry & Vikas Arige & Muyuan Chen & Alexander B. Seryshev & Matthew L. Baker & Steven J. Ludtke & David I. Yule & Irina I. Serysheva, 2022. "Conformational motions and ligand-binding underlying gating and regulation in IP3R channel," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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