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Isoform-selective disruption of AKAP-localized PKA using hydrocarbon stapled peptides.

Research paper by Yuxiao Y Wang, Tienhuei G TG Ho, Daniela D Bertinetti, Matthias M Neddermann, Eugen E Franz, Gary C H GC Mo, Lewis P LP Schendowich, Avinash A Sukhu, Raybun C RC Spelts, Jin J Zhang, Friedrich W FW Herberg, Eileen J EJ Kennedy

Indexed on: 16 Jan '14Published on: 16 Jan '14Published in: ACS Chemical Biology



Abstract

A-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.