Inositol 1,4,5-Trisphosphate Receptor

From Proteopedia

Revision as of 00:23, 18 March 2010

Shannon King

Inositol 1,4,5-trisphosphate receptor binding protein is a ubiquitous protein involved in the Ca²⁺ signalling processes in a variety of organisms ^[1]

Overall Structure

The specific type of inositol 1,4,5-trisphosphate receptor (InsP₃R) protein discussed here is the mouse type one 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 overall structure with the ligand bound can be seen here:

Image:1n4k1.PNG

Domain Structure

The protein fold of the β-domain can also be called the β-trefoil. This element is present in other proteins as well, including fibroblast growth factors and mannose receptors.^[1] In the case of the InsP₃R β-trefoil, the structure was found to be very similar to the β-trefoil of the mannose receptor. In the β-domain of InsP₃R1, three of six two-stranded hairpins come together to form a barrel and the other three form a triangular cap for the barrel.^[1]

The α-domain of InsP₃R shows a high degree of homology with an element called an armidillo repeat fold found in proteins such as β-catenin and importins.^[1] In β-catenin and importins, the armadillo repeat functions as a motif for protein-protein interactions.^[1] Within the α-domain of mouse InsP₃R1, there are two large, highly conserved surfaces.^[1] Both regions are rich in aromatic residues, indicating that they may function as interaction sites for parts of the receptor or other cellular proteins.^[1] A possible option for this kind of binding domain would be the InsP₃ binding suppressor domain present at the N-terminus which reduces the binding affinity for the InsP₃ ligand.^[1] The structures of the two domains can be seen in the image below.

Image:Fold regions.PNG

Binding the InsP₃ Ligand

Highly basic amino acid residues are present on both domains and are responsile for the binding of InsP₃ to InsP₃R.^[1] 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] 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]

A representation of the InsP₃R ligand, InsP₃

Function