Ca2+ signalling processes
Inositol 1,4,5-Trisphosphate Receptor binding protein is a ubiquitous protein involved in the Ca2+ signalling processes in a variety of organisms [1]. The specific type of inositol 1,4,5-trisphosphate receptor (InsP3R) protein discussed here is the mouse type 1 InsP3R, also called InsP3R1. This polypeptide contains three major regions: the amino terminal inositol 1,4,5-trisphosphate (InsP3) binding region, the central modulatory region, and the carboxy-terminus channel region.[1] The protein forms an L-shaped structure composed of two asymmetric domains perpendicular to each other.[1] The N-terminal domain is made up of 12 β-strands and 2 single-turn helices, which come together to form a barrel.[1] The C-terminal end is quite different, consisting of a bundle made of eight α-helices.[1] The interface of the two domains is lined with basic residues and forms the receptor site for InsP3.[1] The InsP3R protein does not belong to a superfamily of proteins. The receptor is thought to span the membrane 6 times, leaving the C-terminus in the cytoplasm. The InsP3 ligand sits between the two domains of the protein. Highly basic amino acid residues are present on both domains and are responsible for the binding of InsP3 to InsP3R.[1] Since the InsP3 ligand is highly charged, it is very likely to interact with the positively charged amino acids present in the N-terminus InsP3-binding domain. In binding, water molecules are involved in hydrogen bonding between InsP3 and its receptor as well as interactions between protein side chains and phosphorous.[1] Active site (water molecules shown as red spheres). Coordination of phosphorous groups is mediated by residues in both the β-domain and α-domain. The hydroxyl groups of InsP3 play a small role in binding to InsP3.[1] Additionally, 9 out of 12 Arg/Lys residues play a very important role in ligand binding and salt bridges to stabilize between the domain regions.[1] The non-basic residues T266, T267, G268, and Y567 are also integral in InsP3 coordination: if T267, G268 or Y567 residues are mutated then there will be a significant reduction in ligand binding.[1] In all likelihood, the InsP3-binding site has been found to be made up of multiple sequences present throughout the N-terminal area of the protein. This makes the tertiary structure of the protein and proper folding absolutely integral to the function: if the protein does not fold correctly, then the multiple sequences of the protein making up the binding region cannot come together to be at all functional in binding the InsP3 ligand.
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