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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Hydrocarbons
Cyclic AMP-Dependent Protein Kinases
Protein Kinases
Protein Isoforms
Phosphotransferases
Peptides
Proteins
Dimerization
Cell Line
Cells

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., ... 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

Isoform-selective disruption of AKAP-localized PKA using hydrocarbon stapled peptides. / Wang, Yuxiao; Ho, Tienhuei G.; Bertinetti, Daniela; Neddermann, Matthias; Franz, Eugen; Mo, Gary C H; Schendowich, Lewis P.; Sukhu, Avinash; Spelts, Raybun C.; Zhang, Jin; Herberg, Friedrich W.; Kennedy, Eileen J.

In: ACS Chemical Biology, Vol. 9, No. 3, 21.03.2014, p. 635-642.

Research output: Contribution to journalArticle

Wang, Y, Ho, TG, Bertinetti, D, Neddermann, M, Franz, E, Mo, GCH, Schendowich, LP, Sukhu, A, Spelts, RC, Zhang, J, Herberg, FW & Kennedy, EJ 2014, 'Isoform-selective disruption of AKAP-localized PKA using hydrocarbon stapled peptides', ACS Chemical Biology, vol. 9, no. 3, pp. 635-642. https://doi.org/10.1021/cb400900r
Wang Y, Ho TG, Bertinetti D, Neddermann M, Franz E, Mo GCH et al. Isoform-selective disruption of AKAP-localized PKA using hydrocarbon stapled peptides. ACS Chemical Biology. 2014 Mar 21;9(3):635-642. https://doi.org/10.1021/cb400900r
Wang, Yuxiao ; Ho, Tienhuei G. ; Bertinetti, Daniela ; Neddermann, Matthias ; Franz, Eugen ; Mo, Gary C H ; Schendowich, Lewis P. ; Sukhu, Avinash ; Spelts, Raybun C. ; Zhang, Jin ; Herberg, Friedrich W. ; Kennedy, Eileen J. / Isoform-selective disruption of AKAP-localized PKA using hydrocarbon stapled peptides. In: ACS Chemical Biology. 2014 ; Vol. 9, No. 3. pp. 635-642.
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