Inositol 1,4,5-Trisphosphate Receptor: Difference between revisions

<StructureSection load='1n4K' size='350' side='right' caption='Mouse inositol triphosphate receptor ligand-binding core complex with its ligand inositol triphosphate (PDB entry [[1n4k]])' scene=''>

==Function==

=== 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.<ref name="mainpaper"/>  In the case of the InsP₃R 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 InsP₃R1, 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"/>

The InsP₃ <scene name='Sandbox_170/1n4k/8'>ligand</scene> sits between the two domains of the protein.  Highly <scene name='38/382942/Ip3_binding_pocket/1'>basic amino acid residues</scene> are present on both domains and are responsible for the binding of InsP₃ to InsP₃R.<ref name="mainpaper"/>  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.<ref name="functionref"/> In binding, water molecules are involved in hydrogen bonding between InsP₃ 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 InsP₃ play a small role in binding to InsP₃.<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 InsP₃ coordination: if T267, G268 or Y567 residues are mutated then there will be a significant reduction in ligand binding.<ref name="mainpaper"/>  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.<ref name="functionref"/>  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.

[[Image:Ligand1.PNG| thumb|Inositol 1,4,5-trisphosphate]]

The InsP₃R protein can autophosphorylate itself and is a substrate for multiple protein kinases.<ref name="functionref"/>  These kinases include cyclic AMP-dependent protein kinase (PKA), cyclic GMP-dependent protein kinase (PKG) and others.<ref name="functionref"/>  The protein kinases are thought to interact with the InsP₃ receptor by controlling the sensitivity to Ca²⁺ in different tissues as well as affecting the sensitivity of InsP₃ itself to Ca²⁺.<ref name="functionref"/>

===3D structures of inositol 1,4,5-trisphosphate receptor===

[[3jrr]] – mInsP3R III ligand-binding suppressor domain – mouse<br />