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

doi:10.1021/cb400900r

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

55 Scopus citations

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 language	English (US)
Pages (from-to)	635-642
Number of pages	8
Journal	ACS Chemical Biology
Volume	9
Issue number	3
DOIs	https://doi.org/10.1021/cb400900r
State	Published - Mar 21 2014

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
General Medicine

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10.1021/cb400900r

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@article{f52a188e717244fea805cf18969bc20e,

title = "Isoform-selective disruption of AKAP-localized PKA using hydrocarbon stapled peptides",

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.",

author = "Yuxiao Wang and Ho, {Tienhuei G.} and Daniela Bertinetti and Matthias Neddermann and Eugen Franz and Mo, {Gary C H} and Schendowich, {Lewis P.} and Avinash Sukhu and Spelts, {Raybun C.} and Jin Zhang and Herberg, {Friedrich W.} and Kennedy, {Eileen J.}",

year = "2014",

month = mar,

day = "21",

doi = "10.1021/cb400900r",

language = "English (US)",

volume = "9",

pages = "635--642",

journal = "ACS Chemical Biology",

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T1 - Isoform-selective disruption of AKAP-localized PKA using hydrocarbon stapled peptides

AU - Wang, Yuxiao

AU - Ho, Tienhuei G.

AU - Bertinetti, Daniela

AU - Neddermann, Matthias

AU - Franz, Eugen

AU - Mo, Gary C H

AU - Schendowich, Lewis P.

AU - Sukhu, Avinash

AU - Spelts, Raybun C.

AU - Zhang, Jin

AU - Herberg, Friedrich W.

AU - Kennedy, Eileen J.

PY - 2014/3/21

Y1 - 2014/3/21

N2 - 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.

AB - 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.

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

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