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Isoform-Selective Disruption of AKAP-Localized PKA Using Hydrocarbon Stapled Peptides

[Image: see text] 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 betwee...

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Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3985448/
https://www.ncbi.nlm.nih.gov/pubmed/24422448
http://dx.doi.org/10.1021/cb400900r
Descripción
Sumario:[Image: see text] 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.