PKA-Type i Selective Constrained Peptide Disruptors of AKAP Complexes

Yuxiao Wang, Tienhuei G. Ho, Eugen Franz, Jennifer S. Hermann, F. Donelson Smith, Heidi Hehnly, Jessica L. Esseltine, Laura E. Hanold, Mandi M. Murph, Daniela Bertinetti, John D. Scott, Friedrich W. Herberg, Eileen J. Kennedy

Research output: Contribution to journalArticle

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1502-1510
Number of pages9
JournalACS Chemical Biology
Volume10
Issue number6
DOIs
StatePublished - Jun 19 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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    Wang, Y., Ho, T. G., Franz, E., Hermann, J. S., Smith, F. D., Hehnly, H., Esseltine, J. L., Hanold, L. E., Murph, M. M., Bertinetti, D., Scott, J. D., Herberg, F. W., & Kennedy, E. J. (2015). PKA-Type i Selective Constrained Peptide Disruptors of AKAP Complexes. ACS Chemical Biology, 10(6), 1502-1510. https://doi.org/10.1021/acschembio.5b00009