Inositol 1,4,5-Trisphosphate Receptor

Shannon King

Please do NOT make changes to this Sandbox until after April 23, 2010. Sandboxes 151-200 are reserved until then for use by the Chemistry 307 class at UNBC taught by Prof. Andrea Gorrell.

spinqualitylabelsall models Inositol 1,4,5-trisphosphate receptor. The red and orange molecule represents the ligand of the protein, inositol 1,4,5-trisphosphate Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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

Overall StructureOverall 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. 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. The C-terminal end is quite different, consisting of a bundle made of eight α-helices. The interface of the two domains is lined with basic residues and forms the receptor site for InsP₃. The overall structure with the ligand bound can be seen here:

File:1n4k1.PNG

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Domain StructureDomain 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. 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.

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. In β-catenin and importins, the armadillo repeat functions as a motif for protein-protein interactions. Within the α-domain of mouse InsP₃R1, there are two large, highly conserved surfaces. Both regions are rich in aromatic residues, indicating that they may function as interaction sites for parts of the receptor or other cellular proteins. 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.

File:Fold regions.PNG

The above image is from Bosanac et al.'s 2002 paper "Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand." This image shows a cartoon representation of both the β-trefoil and α-domain armadillo repeats.

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Binding the InsP₃ LigandBinding the InsP3 Ligand

Highly basic amino acid residues are present on both domains and are responsile for the binding of InsP₃ to InsP₃R. In binding, water molecules are involved in hydrogen bonding between InsP₃ and its receptor as well as interactions between protein side chains and phosphorous. 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. 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. 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.

Inositol 1,4,5-trisphosphate

FunctionFunction

Role in Ca²⁺ regulationRole in Ca2+ regulation

The presence of inositol 1,4,5-trisphosphate functions to increase the cytosolic concentration of Ca²⁺. The InsP₃ is formed at the plasma membrane, diffuses into the cytosol, and binds to the InsP₃ receptor which is found in the membrane of intracellular Ca²⁺ stores. The release of Ca²⁺ can propagate to other cells and can help to coordinate the functionality of organ systems. Areas of the body rich in the InsP₃ receptor are the cerebellum and, more specifically, the endoplasmic reticulum, and even the plasma membrane and nuclei of some tissues. Recent results also suggest that InsP₃ receptors work in intrinsic Ca²⁺ channel activity.

RegulationRegulation

Sequences within the receptor protein have been found to interact with accessory proteins. Additionally, there are sites for ATP binding and for phosphorylation. All of these interactions would play a role in the regulation of the InsP₃ receptor protein.

A very important property of the receptor is that it is regulated by Ca²⁺ concentrations. Lower concentrations make the receptor more sensitive to InsP₃ while high concentrations can inhibit the receptor activity. Also, the receptor itself can bind Ca³ itself at more than one site. A Ca²⁺ binding site within the ligand binding domain may even suggest that these Ca²⁺ binding sites are involved in the effects Ca^{2+ has on InsP₃ binding to its ligand.}

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