Aufsatz in einer Fachzeitschrift
Isoform-Selective Disruption of AKAP-localized PKA Using Hydrocarbon Stapled Peptides
Details zur Publikation
Autor(inn)en: | Wang, Y.; Ho, T.; Bertinetti, D.; Neddermann, M.; Franz, E.; Mo, G.; Schendowich, L.; Sukhu, A.; Spelts, R.; Zhang, J.; Herberg, F.; Kennedy, E. |
Publikationsjahr: | 2014 |
Zeitschrift: | ACS Chemical Biology |
Seitenbereich: | 635-42 |
Jahrgang/Band : | 9 |
ISSN: | 1554-8929 |
DOI-Link der Erstveröffentlichung: |
Zusammenfassung, 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.
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.
Schlagwörter
coprip, herberg
