Journal article
PKA-Type I Selective Constrained Peptide Disruptors of AKAP Complexes
Publication Details
Authors: | Wang, Y.; Ho, T.; Franz, E.; Hermann, J.; Smith, F.; Hehnly, H.; Esseltine, J.; Hanold, L.; Murph, M.; Bertinetti, D.; Scott, J.; Herberg, F.; Kennedy, E. |
Publisher: | AMER CHEMICAL SOC |
Publication year: | 2015 |
Journal: | ACS Chemical Biology |
Pages range : | 1502-1510 |
Volume number: | 10 |
Start page: | 1502 |
End page: | 1510 |
Number of pages: | 9 |
ISSN: | 1554-8929 |
eISSN: | 1554-8937 |
DOI-Link der Erstveröffentlichung: |
Abstract
A-Kinase Anchoring Proteins (AKAPs) coordinate complex signaling events by serving as spatiotemporal modulators of cAMP-dependent protein kinase activity in cell. Although AKAPs organize a plethora of diverse pathways, their cellular roles are often elusive due to the dynamic nature Of these signaling complexes. AKAPs can interact with the type I or type II PKA holoenzymes by virtue of high-affinity interactions with the R-subunits. As a means to delineate AKAP-mediated PKA signaling in cells, we sought-to develop isoform-selective disruptors of AKAP signaling. Here, we report the development of conformationally constrained peptides named RI-STapled Anchoring Disruptors (RI-STADs) that target the docking/dimerization domain of the type 1 regulatory subunit of PICA. These high-affinity peptides ate isoform-selective for the RI isoforms, can outcompete binding by the classical AKAP disruptor Ht31, and can selectively displace RI alpha, but not RII alpha, from binding the dual-specific AKAP149 complex. Importantly, these peptides are-cell-permeable and disrupt Type I PICA-mediated phosphorylation events in the context of live cells. Hence, RI-STAD peptides are versatile cellular tool's to selectively probe anchored type I PICA signaling events.
A-Kinase Anchoring Proteins (AKAPs) coordinate complex signaling events by serving as spatiotemporal modulators of cAMP-dependent protein kinase activity in cell. Although AKAPs organize a plethora of diverse pathways, their cellular roles are often elusive due to the dynamic nature Of these signaling complexes. AKAPs can interact with the type I or type II PKA holoenzymes by virtue of high-affinity interactions with the R-subunits. As a means to delineate AKAP-mediated PKA signaling in cells, we sought-to develop isoform-selective disruptors of AKAP signaling. Here, we report the development of conformationally constrained peptides named RI-STapled Anchoring Disruptors (RI-STADs) that target the docking/dimerization domain of the type 1 regulatory subunit of PICA. These high-affinity peptides ate isoform-selective for the RI isoforms, can outcompete binding by the classical AKAP disruptor Ht31, and can selectively displace RI alpha, but not RII alpha, from binding the dual-specific AKAP149 complex. Importantly, these peptides are-cell-permeable and disrupt Type I PICA-mediated phosphorylation events in the context of live cells. Hence, RI-STAD peptides are versatile cellular tool's to selectively probe anchored type I PICA signaling events.
