The discovery and structural investigation of the IP 3 receptor and the associated IRBIT protein

Abstract

The IP 3 receptor (IP 3R) is a Ca 2+ channel that releases Ca 2+ from the endoplasmic reticulum (ER) and plays a variety of roles in cell functions. This receptor was discovered as a developmentally regulated glyco-phosphoprotein, known as P400, which was absent in cerebellar mutant mice. The IP 3R has three different isoforms in vertebrates, and each IP 3R is composed of different subdomains. The affinities of the IP 3-binding core of the three isoforms of the IP 3R for IP 3 are similar. The N-terminal IP 3-binding suppressor region of each isoform is responsible for its isoform-specific IP 3-binding affinity. IP 3 binding to the IP 3-binding core leads to a conformational change, resulting in direct interactions of tyrosine-168 (in IP 3R1)/tryptophane-168 (in IP 3R2 and 3) in the N-terminal suppressor region with the loop region of transmembrane 4-5. The suppressor region and C-terminal -portion which associate with nearly 20 signaling molecules are located at the areas near the channel pore. The area including suppressor region and C-terminal portion are regarded as hot spots for the regulating opening and closing of the channel pore. A pseudo-ligand of the IP 3R, known as IRBIT (IP 3R binding protein released with inositol 1,4,5-trisphosphate), that interacts with the IP 3-binding core domain of the IP 3R was discovered. IRBIT not only regulates Ca 2+ release by binding to the IP 3-binding core domain but also regulates the acid-base balance by binding to various ion transporters, such as pancreas-type NBC1 (pNBC1) and CFTR. Most of the associated proteins bind to these areas and regulate IP 3R channel gating. Cryo-electron microscopy shows a balloon-like structure, which has vacancy inside the IP 3R with multi-porous surface area. The unique 3-dimensional structure of the IP 3R is convenient for associating with many IP 3R-associated proteins. Therefore, the IP 3R serves as a signaling hub, which forms macromolecular complex with various molecules. © 2012 Springer Science+Business Media B.V.