• Yuxiao Wang, Tienhuei G Ho, Daniela Bertinetti, Matthias Neddermann, Eugen Franz, Gary C H Mo, Lewis P Schendowich, Avinash Sukhu, Raybun C Spelts, Jin Zhang, Friedrich W Herberg, and Eileen J Kennedy.
• Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia , Athens, Georgia 30602, United States.
• ACS Chem. Biol. 2014 Mar 21; 9 (3): 635-42.

AbstractA-kinase anchoring proteins (AKAPs) play an important role in the spatial and temporal regulation of protein kinase A (PKA) by scaffolding critical intracellular signaling complexes. Here we report the design of conformationally constrained peptides that disrupt interactions between PKA and AKAPs in an isoform-selective manner. Peptides derived from the A Kinase Binding (AKB) domain of several AKAPs were chemically modified to contain an all-hydrocarbon staple and target the docking/dimerization domain of PKA-R, thereby occluding AKAP interactions. The peptides are cell-permeable against diverse human cell lines, are highly isoform-selective for PKA-RII, and can effectively inhibit interactions between AKAPs and PKA-RII in intact cells. These peptides can be applied as useful reagents in cell-based studies to selectively disrupt AKAP-localized PKA-RII activity and block AKAP signaling complexes. In summary, the novel hydrocarbon-stapled peptides developed in this study represent a new class of AKAP disruptors to study compartmentalized RII-regulated PKA signaling in cells.

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