Association of the Inositol (1,4,5)-Trisphosphate Receptor Ligand Binding Site with Phosphatidylinositol (4,5)-Bisphosphate and Adenophostin A |
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| Affiliation: | 1. Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, 75235;2. Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, 75235;3. Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7UE, United Kingdom;1. Department of Biomedical Sciences, University of Padova, Padova, Italy;2. Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy;3. Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy;4. Veneto Institute of Molecular Medicine, Padova, Italy;1. School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, PR China;2. Instrumental Analysis and Research Center, Shanghai University, Shanghai 200444, PR China;1. Food Science Department, Federal University of Lavras, CEP 37200-000 Lavras, MG, Brazil;2. Biology Department, Federal University of Lavras, CEP 37200-000 Lavras, MG, Brazil;3. Undergraduate Course in Coffee Technology, Federal Institute of Espírito Santo - IFES, CEP 29520-000 Alegre, ES, Brazil;1. College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China;2. National Beef Cattle Improvement Center of Northwest A&F University, Yangling, Shaanxi 712100, PR China |
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| Abstract: | The inositol 1,4,5-trisphosphate receptor (InsP3R) is activated by InsP3 binding to amino-terminal ligand binding domain (InsP3R-N). Recently we reported functional coupling of phosphatidylinositol (4,5)-bisphosphate (PIP2) to the InsP3R. Specific binding of PIP2 to InsP3R-N domain was postulated as a part of the InsP3R-PIP2 functional coupling model. Here we utilized bacterially expressed and purified InsP3R-N domain to characterize its binding specificity for InsP3, Adenophostin A (AdA) and the water-soluble PIP2 analog dioctanoyl-(4,5)PIP2 (ShPIP2). Obtained data led us to conclude that specific InsP3, AdA, and ShPIP2 binding sites are located within the InsP3R-N domain, that the extra receptor binding element responsible for enhanced binding of AdA is an integral part of the InsP3R-N domain, that ShPIP2 is able to displace InsP3 from the InsP3R-N, but InsP3 or AdA is unable to completely displace ShPIP2. These results support the InsP3R-PIP2 functional coupling model and provide novel insights into InsP3R ligand specificity. |
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