Molecular Determinants of the Interaction between the Inositol 1,4,5-Trisphosphate Receptor-associated cGMP Kinase Substrate (IRAG) and cGMP Kinase Iβ* 210

By A. Ammendola, A. Geiselhöringer, F. Hofmann, J. Schlossmann. Journal of Biological Chemistry, 2001

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Cyclic GMP-dependent protein kinase I (cGKI) affects the inositol 1,4,5-trisphosphate (InsP3)-dependent release of intracellular calcium by phosphorylation of IRAG (inositol 1,4,5-trisphophate receptor-associated cGMP kinase substrate). IRAG is present in a macromolecular complex with the InsP3 receptor type I (InsP3RI) and cGKIβ. The specificity of the interaction between these three proteins was investigated by using the yeast two-hybrid system and by co-precipitation of expressed proteins. The amino-terminal region containing the leucine zipper (amino acids 1–53) of cGKIβ but not that of cGKIα or cGKII interacted with the sequence between amino acids 152 and 184 of IRAG in vitroand in vivo most likely through electrostatic interaction. cGKIβ did not interact with the InsP3RI, but co-precipitated the InsP3RI in the presence of IRAG indicating that IRAG bound to the InsP3RI and to cGKIβ. cGKIβ phosphorylated up to four serines in IRAG. Mutation of these four serines to alanine showed that cGKIβ-dependent phosphorylation of Ser696 is necessary to decrease calcium release from InsP3-sensitive stores. These results show that cGMP induced reduction of cytosolic calcium concentrations requires cGKIβ and phosphorylation of Ser696 of IRAG.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ee728483a63d413a56648be83b6f4c34e7e85b40

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