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| Inositol 1,4,5-trisphosphate receptor binding protein is a ubiquitous protein involved in the Ca<sup>2+</sup> signalling processes in a variety of organisms <ref name="mainpaper">PMID:12442173</ref> | | Inositol 1,4,5-trisphosphate receptor binding protein is a ubiquitous protein involved in the Ca<sup>2+</sup> signalling processes in a variety of organisms <ref name="mainpaper">PMID:12442173</ref> |
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| == Overall Structure ==
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| The specific type of inositol 1,4,5-trisphosphate receptor (InsP<sub>3</sub>R) protein discussed here is the mouse type 1 InsP<sub>3</sub>R, also called InsP<sub>3</sub>R1. This polypeptide contains three major regions: the amino terminal inositol 1,4,5-trisphosphate (InsP<sub>3</sub>) binding region, the central modulatory region, and the carboxy-terminus channel region.<ref name="mainpaper"/> The protein forms an L-shaped structure composed of two asymmetric domains perpendicular to each other.<sup>[1]</sup> The N-terminal domain is made up of 12 β-strands and 2 single-turn helices, which come together to form a barrel.<ref name="mainpaper"/> The C-terminal end is quite different, consisting of a bundle made of eight α-helices.<ref name="mainpaper"/> The interface of the two domains is lined with basic residues and forms the receptor site for InsP<sub>3</sub>.<ref name="mainpaper"/> The InsP<sub>3</sub>R protein does not belong to a superfamily of proteins. The overall structure with the ligand bound can be seen here:
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| [[Image:1n4k1.PNG]]
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| === Domain Structure ===
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| 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.<ref name="mainpaper"/> In the case of the InsP<sub>3</sub>R β-trefoil, the structure was found to be very similar to the β-trefoil of the mannose receptor.<ref name="mainpaper"/> In the β-domain of InsP<sub>3</sub>R1, three of six two-stranded hairpins come together to form a barrel and the other three form a triangular cap for the barrel.<ref name="mainpaper"/>
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| The α-domain of InsP<sub>3</sub>R shows a high degree of homology with an element called an armidillo repeat fold found in proteins such as β-catenin and importins.<ref name="mainpaper"/> In β-catenin and importins, the armadillo repeat functions as a motif for protein-protein interactions.<ref name="mainpaper"/> Within the α-domain of mouse InsP<sub>3</sub>R1, there are two large, highly conserved surfaces.<ref name="mainpaper"/> Both regions are rich in aromatic residues, indicating that they may function as interaction sites for parts of the receptor or other cellular proteins.<ref name="mainpaper"/> A possible option for this kind of binding domain would be the InsP<sub>3</sub> binding suppressor domain present at the N-terminus which reduces the binding affinity for the InsP<sub>3</sub> ligand.<ref name="mainpaper"/>
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| [[Image:fold regions.PNG]]
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| 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."<ref name="mainpaper"/> This image shows a cartoon representation of both the β-trefoil and α-domain armadillo repeats.
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| === Binding the InsP<sub>3</sub> Ligand ===
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| Highly basic amino acid residues are present on both domains and are responsile for the binding of InsP<sub>3</sub> to InsP<sub>3</sub>R.<ref name="mainpaper"/> In binding, water molecules are involved in hydrogen bonding between InsP<sub>3</sub> and its receptor as well as interactions between protein side chains and phosphorous.<ref name="mainpaper"/> Coordination of phosphorous groups is mediated by residues in both the β-domain and α-domain. The hydroxyl groups of InsP<sub>3</sub> play a small role in binding to InsP<sub>3</sub>.<ref name="mainpaper"/> 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.<ref name="mainpaper"/> The non-basic residues T266, T267, G268, and Y567 are also integral in Insp<sub>3</sub> coordination: if T267, G268 or Y567 residues are mutated then there will be a significant reduction in ligand binding.<ref name="mainpaper"/>
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| [[Image:Ligand1.PNG| thumb|Inositol 1,4,5-trisphosphate]]
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| == Function ==
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| === Role in Ca<sup>2+</sup> regulation ===
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| The presence of inositol 1,4,5-trisphosphate functions to increase the cytosolic concentration of Ca<sup>2+</sup>.<ref name="functionref">PMID:10378086</ref> The InsP<sub>3</sub> is formed at the plasma membrane, diffuses into the cytosol, and binds to the InsP<sub>3</sub> receptor which is found in the membrane of intracellular Ca<sup>2+</sup> stores.<ref name="functionref"/> The release of Ca<sup>2+</sup> can propagate to other cells and can help to coordinate the functionality of organ systems.<ref name="functionref"/> Areas of the body rich in the InsP<sub>3</sub> receptor are the cerebellum and, more specifically, the endoplasmic reticulum, and even the plasma membrane and nuclei of some tissues.<ref name="functionref"/> Recent results also suggest that InsP<sub>3</sub> receptors work in intrinsic Ca<sup>2+</sup> channel activity.<ref name="functionref"/>
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| === Regulation of receptor activity ===
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| Sequences within the receptor protein have been found to interact with accessory proteins. Additionally, there are sites for ATP binding and for phosphorylation.<ref name="functionref"/> All of these interactions would play a role in the regulation of the InsP<sub>3</sub> receptor protein.
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| A very important property of the receptor is that it is regulated by Ca<sup>2+</sup> concentrations. Lower concentrations make the receptor more sensitive to InsP<sub>3</sub> while high concentrations can inhibit the receptor activity.<ref name="functionref"/> Also, the receptor itself can bind Ca<sup>3</sup> itself at more than one site. A Ca<sup>2+</sup> binding site within the ligand binding domain may even suggest that these Ca<sup>2+</sup> binding sites are involved in the effects Ca<sup>2+</sup> has on InsP<sub>3</sub> binding to its ligand.
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| The method of regulation by ATP on the receptor is very similar to that of Ca<sup><2+</sup>. Increased ATP concentrations increase receptor activity whereas higher concentrations decrease receptor activity.<ref name="functionref"/> The binding sites responsible for such activity are likely consensus adenine-nucleotide-binding motifsInositol 1,4,5-trisphosphate receptor binding protein is a ubiquitous protein involved in the Ca<sup>2+</sup> signalling processes in a variety of organisms <ref name="mainpaper">PMID:12442173</ref>
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| == Overall Structure == | | == Overall Structure == |