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

<table style="background-color:#ffffc0" cellpadding="8" width="95%" border="0"><tr><td>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. [[User:Andrea Gorrell|Andrea Gorrell]].</td></tr>

 

{{STRUCTURE_1n4k |  PDB=1n4k  |  SCENE= }}

 

 

Inositol 1,4,5-trisphosphate receptor binding protein is a ubiquitous protein involved in the Ca²⁺ signalling processes in a variety of organisms <ref name="mainpaper">PMID:12442173</ref>

 

 

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.^[1]  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 overall structure with the ligand bound can be seen here:

 

 

[[Image:1n4k1.PNG]]

 

 

 

 

 

 

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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.

 

The method of regulation by ATP on the receptor is very similar to that of Ca^<2+.  Increased ATP concentrations increase receptor activity whereas higher concentrations decrease receptor activity.<ref name="functionref"/>  The stimulatory activity of ATP likely occurs through consensus adenine nucleotide-binding motifs.<ref name="functionref"/>  The inhibitory effect of ATP is thought to arise through its charged nature, acting as a competitive antagonist at the InsP₃-binding site.<ref name="functionref"/>

 

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