Structural basis for activation and gating of IP3 receptors

Emily A. Schmitz, Hirohide Takahashi and Erkan Karakas ()
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Emily A. Schmitz: Vanderbilt University, School of Medicine
Hirohide Takahashi: Vanderbilt University, School of Medicine
Erkan Karakas: Vanderbilt University, School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-9

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29073-2

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