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

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.<ref name="mainpaper"/>  The protein forms an L-shaped structure composed of two asymmetric domains perpendicular to each other.<ref name="mainpaper"/>  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 InsP₃.<ref name="mainpaper"/>  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.<ref name="functionref"/>   

The InsP₃ <scene name='Sandbox_170/1n4k/8'>ligand</scene> 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.<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.