PKA-type I selective constrained peptide disruptors of AKAP complexes

ACS Chemical Biology
Yuxiao WangEileen J Kennedy

Abstract

A-Kinase Anchoring Proteins (AKAPs) coordinate complex signaling events by serving as spatiotemporal modulators of cAMP-dependent protein kinase activity in cells. 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 PKA. These high-affinity peptides are isoform-selective for the RI isoforms, can outcompete binding by the classical AKAP disruptor Ht31, and can selectively displace RIα, but not RIIα, from binding the dual-specific AKAP149 complex. Importantly, these peptides are cell-permeable and disrupt Type I PKA-mediated phosphorylation events in the context of live cells. Hence, RI-STAD peptides are versatile cellular tools to selectively probe anchored type I PKA signaling events.

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Citations

Sep 20, 2015·Cellular Signalling·Alessandro DemaEnno Klussmann
Dec 22, 2015·Chemistry & Biology·Thomas M MoonWolfgang R Dostmann
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Nov 2, 2016·ACS Chemical Biology·Yana K RennieAndrew G Jamieson
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Apr 2, 2020·Chemistry : a European Journal·Danielle L PatersonMargaret A Brimble
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Jul 7, 2020·Annual Review of Pharmacology and Toxicology·Paula J Bucko, John D Scott
Apr 27, 2020·Cellular Signalling·Caroline R SussmanVicente E Torres
Aug 31, 2021·RSC Chemical Biology·Ameya J LimayeEileen J Kennedy

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