Inositol trisphosphate receptor

Discovery

The InsP3 receptor was first purified from rat cerebellum by neuroscientists Surachai Supattapone and Solomon Snyder at Johns Hopkins University School of Medicine.

The cDNA of the InsP3 receptor was first cloned in the laboratory of Katsuhiko Mikoshiba. The initial sequencing was reported as an unknown protein enriched in the cerebellum called P400. The large size of this open reading frame indicated a molecular weight similar to the protein purified biochemically, and soon thereafter it was confirmed that the protein p400 was in fact the inositol trisphosphate receptor.

Distribution

The receptor has a broad tissue distribution but is especially abundant in the cerebellum. Most of the InsP3Rs are found integrated into the endoplasmic reticulum.

Structure

Several X-ray crystallographic and electron cryomicroscopic (cryo-EM) structures of IP3Rs from mouse, rat, and human have defined the overall architecture of the channel. The 1.2 MDa C4-symmetric assembly consists of an ER-embedded transmembrane domain (TMD) in a domain-swapped 6 transmembrane (6TM) cation channel fold that is capped by a large cytosolic domain (CD). In this manner, IP3Rs share significant homology with the much larger and distantly-related RyRs. The CD contains all known ligand binding sites, including the IP3 binding site, two Ca2+ binding sites, an adenine nucleotide binding site, and a C2H2 Zn2+ finger fold. A comprehensive Ca2+-dependent conformational landscape has been defined by cryo-EM.

References

References

1. (January 2005). "Crystal structure of the ligand binding suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor". Molecular Cell.
2. (December 2002). "Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand". Nature.
3. (June 1997). "Structure and function of inositol 1,4,5-trisphosphate receptor". Japanese Journal of Pharmacology.
4. (January 1988). "Solubilization, purification, and characterization of an inositol trisphosphate receptor". The Journal of Biological Chemistry.
5. (July 1989). "Nucleotide sequence of cDNA encoding P400 protein in the mouse cerebellum". Nucleic Acids Research.
6. (November 1989). "Primary structure and functional expression of the inositol 1,4,5-trisphosphate-binding protein P400". Nature.
7. (December 2002). "Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand". Nature.
8. (September 2011). "Apo and InsP₃-bound crystal structures of the ligand-binding domain of an InsP₃ receptor". Nature Structural & Molecular Biology.
9. (January 2012). "Structural and functional conservation of key domains in InsP3 and ryanodine receptors". Nature.
10. (November 2015). "Gating machinery of InsP3R channels revealed by electron cryomicroscopy". Nature.
11. (August 2018). "Structural basis for the regulation of inositol trisphosphate receptors by Ca²⁺ and IP₃". Nature Structural & Molecular Biology.
12. (December 2018). "Cryo-EM reveals ligand induced allostery underlying InsP₃R channel gating". Cell Research.
13. (February 2020). "Cryo-EM structure of human type-3 inositol triphosphate receptor reveals the presence of a self-binding peptide that acts as an antagonist". The Journal of Biological Chemistry.
14. (May 2021). "Cryo-EM structure of type 1 IP₃R channel in a lipid bilayer". Communications Biology.
15. (March 2022). "Structural basis for activation and gating of IP₃ receptors". Nature Communications.
16. (November 2022). "Conformational motions and ligand-binding underlying gating and regulation in IP₃R channel". Nature Communications.
17. (January 2022). "Calcium-release channels: structure and function of IP₃ receptors and ryanodine receptors". Physiological Reviews.
18. (2023-10-28). "Structural titration reveals Ca2+-dependent conformational landscape of the IP3 receptor". Nature Communications.