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

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, Eileen J. Kennedy

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)635-642
Number of pages8
JournalACS Chemical Biology
Volume9
Issue number3
DOIs
StatePublished - Mar 21 2014

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Medicine(all)

Cite this

Wang, Y., Ho, T. G., Bertinetti, D., Neddermann, M., Franz, E., Mo, G. C. H., Schendowich, L. P., Sukhu, A., Spelts, R. C., Zhang, J., Herberg, F. W., & Kennedy, E. J. (2014). Isoform-selective disruption of AKAP-localized PKA using hydrocarbon stapled peptides. ACS Chemical Biology, 9(3), 635-642. https://doi.org/10.1021/cb400900r