Structural basis for activation and gating of IP3 receptors
Emily A Schmitz1,2, Hirohide Takahashi1,2, Erkan Karakas3,4
1Department of Molecular Physiology and Biophysics, Vanderbilt University, School of Medicine, Nashville, TN, 37232, USA.
Nature Communications
|March 18, 2022
Summary
The inositol 1,4,5-triphosphate (IP3) receptor (IP3R) controls cellular calcium (Ca2+) levels. Cryo-EM structures reveal how IP3R opens and closes, detailing the roles of IP3, Ca2+, and ATP in its gating mechanism.
Area of Science:
- Cellular Biology
- Molecular Mechanisms
- Biophysics
Background:
- The inositol 1,4,5-triphosphate (IP3) receptor (IP3R) is crucial for calcium (Ca2+) signaling, regulating Ca2+ release from the endoplasmic reticulum (ER).
- IP3Rs are modulated by IP3, Ca2+, and ATP, but the precise molecular mechanisms of their gating remain elusive.
Purpose of the Study:
- To elucidate the molecular mechanisms of IP3 receptor (IP3R) activation and gating.
- To provide structural insights into how IP3, Ca2+, and ATP interact with IP3R to control channel activity.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was used to determine the structures of the human type-3 IP3R.
- Multiple gating conformations were resolved from a single dataset, including pre-active, active, and inactive states.
Main Results:
- Cryo-EM structures captured the IP3 receptor (IP3R) in distinct conformations: IP3-ATP bound (pre-active, closed), IP3-ATP-Ca2+ bound (active, open), and IP3-ATP-Ca2+ bound (inactive, closed).
- The structures illustrate IP3-primed conformational changes, Ca2+-induced channel opening, and ATP's modulatory role in IP3R gating.
Conclusions:
- These findings provide a detailed molecular understanding of inositol 1,4,5-triphosphate (IP3) receptor activation and gating.
- The structural insights advance our knowledge of calcium (Ca2+) signaling pathways and the function of IP3Rs in cellular processes.
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