Ca2+ signalling processes: Difference between revisions

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Alexander Berchansky

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 <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='38/382942/Cv/1'>
 *[[Inositol 1,4,5-Trisphosphate Receptor]]
+''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>. 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 <scene name='38/382942/N_terminal_domain/1'>amino terminal</scene>  inositol 1,4,5-trisphosphate (InsP<sub>3</sub>) binding region, the central modulatory region, and the <scene name='38/382942/C_terminal_domain/1'>carboxy-terminus channel region</scene>.<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 <scene name='38/382942/Ip3_binding_pocket/1'>receptor site</scene> for InsP<sub>3</sub>.<ref name="mainpaper"/>  The InsP<sub>3</sub>R 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. The InsP<sub>3</sub> <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 InsP<sub>3</sub> to InsP<sub>3</sub>R.<ref name="mainpaper"/>  Since the InsP<sub>3</sub> ligand is highly charged, it is very likely to interact with the positively charged amino acids present in the N-terminus InsP<sub>3</sub>-binding domain. 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"/> <scene name='38/382942/Cv/4'>Active site</scene> (water molecules shown as red spheres). 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"/>  In all likelihood, the InsP<sub>3</sub>-binding site has been found to be made up of multiple sequences present throughout the N-terminal area of the protein. 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 InsP<sub>3</sub> ligand.
 *[[Calcium-dependent protein kinase]]
 *[[Calcium/Calmodulin-dependent protein kinase]]