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.
Description
Isoform-Selective Disruption of AKAP-localized PKA Using Hydrocarbon Stapled Peptides - ACS Chemical Biology (ACS Publications)
%0 Journal Article
%1 wang2014isoformselective
%A Wang, Y.
%A Ho, T. G.
%A Bertinetti, D.
%A Neddermann, M.
%A Franz, E.
%A Mo, G. C. H.
%A Schendowich, L. P.
%A Sukhu, A.
%A Spelts, R. C.
%A Zhang, J.
%A Herberg, F. W.
%A Kennedy, E. J.
%D 2014
%J ACS Chemical Biology
%K herberg myown
%N 3
%P 635-42
%R 10.1021/cb400900r
%T Isoform-Selective Disruption of AKAP-localized PKA Using Hydrocarbon Stapled Peptides
%U http://pubs.acs.org/doi/abs/10.1021/cb400900r
%V 9
%X 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.
@article{wang2014isoformselective,
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. },
added-at = {2014-01-14T21:53:41.000+0100},
author = {Wang, Y. and Ho, T. G. and Bertinetti, D. and Neddermann, M. and Franz, E. and Mo, G. C. H. and Schendowich, L. P. and Sukhu, A. and Spelts, R. C. and Zhang, J. and Herberg, F. W. and Kennedy, E. J.},
biburl = {https://www.bibsonomy.org/bibtex/2fe51a04823de5f304aba9cd153f516ab/biochemie},
description = {Isoform-Selective Disruption of AKAP-localized PKA Using Hydrocarbon Stapled Peptides - ACS Chemical Biology (ACS Publications)},
doi = {10.1021/cb400900r},
eprint = {http://pubs.acs.org/doi/pdf/10.1021/cb400900r},
interhash = {f57767446e98f4b028d94e42a863bc50},
intrahash = {fe51a04823de5f304aba9cd153f516ab},
journal = {ACS Chemical Biology},
keywords = {herberg myown},
number = 3,
pages = {635-42},
timestamp = {2016-11-04T11:17:52.000+0100},
title = {Isoform-Selective Disruption of AKAP-localized PKA Using Hydrocarbon Stapled Peptides},
url = {http://pubs.acs.org/doi/abs/10.1021/cb400900r},
volume = 9,
year = 2014
}