ArticleProceedings of the National Academy of Sciences of the United States of America2003
Designing isoform-specific peptide disruptors of protein kinase A localization.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed.
- A small novel A-kinase anchoring protein (AKAP) that localizes specifically protein kinase A-regulatory subunit I (PKA-RI) to the plasma membrane.The Journal of biological chemistry · 2012Trial
- PRKAR2A/RIIα as a candidate spatial cAMP-PKA signal router in triple-negative breast cancer metastasis: evidence boundaries, competing models and decisive experiments.Molecular biology reports · 2026Review
- Article
- Phosphorylation, compartmentalization, and cardiac function.IUBMB life · 2023Article
- Study of spatiotemporal regulation of kinase signaling using genetically encodable molecular tools.Current opinion in chemical biology · 2022Review
- Biochemical Analysis of AKAP-Anchored PKA Signaling Complexes.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Beyond PKA: Evolutionary and structural insights that define a docking and dimerization domain superfamily.The Journal of biological chemistry · 2021Article
- Cardiac function modulation depends on the A-kinase anchoring protein complex.Journal of cellular and molecular medicine · 2019Review
- Pharmacological Modulation of Mitochondrial CaFrontiers in physiology · 2018Article
- AKAP18:PKA-RIIα structure reveals crucial anchor points for recognition of regulatory subunits of PKA.The Biochemical journal · 2016Article
- Structure of smAKAP and its regulation by PKA-mediated phosphorylation.The FEBS journal · 2016Article
- Defining A-Kinase Anchoring Protein (AKAP) Specificity for the Protein Kinase A Subunit RI (PKA-RI).Chembiochem : a European journal of chemical biology · 2016Article
- Protein Kinase A (PKA) Type I Interacts with P-Rex1, a Rac Guanine Nucleotide Exchange Factor: EFFECT ON PKA LOCALIZATION AND P-Rex1 SIGNALING.The Journal of biological chemistry · 2016Article
- Molecular Mechanisms for cAMP-Mediated Immunoregulation in T cells - Role of Anchored Protein Kinase A Signaling Units.Frontiers in immunology · 2016Review
- Protein Kinase A Opposes the Phosphorylation-dependent Recruitment of Glycogen Synthase Kinase 3β to A-kinase Anchoring Protein 220.The Journal of biological chemistry · 2015Article
- PKA-type I selective constrained peptide disruptors of AKAP complexes.ACS chemical biology · 2015Article
- Fine-tuning Tumor Immunity with Integrin Trans-regulation.Cancer immunology research · 2015Article
- D-AKAP2:PKA RII:PDZK1 ternary complex structure: insights from the nucleation of a polyvalent scaffold.Protein science : a publication of the Protein Society · 2015Article
- Targeting protein-protein interactions in complexes organized by A kinase anchoring proteins.Frontiers in pharmacology · 2015Review
- The genetically encoded tool set for investigating cAMP: more than the sum of its parts.Frontiers in pharmacology · 2015Review
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Authors and funding
10 authors.
Funding
Abstract
A kinase-anchoring proteins (AKAPs) coordinate cAMP-mediated signaling by binding and localizing cAMP-dependent protein kinase (PKA), using an amphipathic helical docking motif. Peptide disruptors of PKA localization that mimic this helix have been used successfully to assess the involvement of PKA in specific signaling pathways. However, these peptides were developed as disruptors for the type II regulatory subunit (RII) even though both RI and RII isoforms can bind to AKAPs and have discrete functions. To evaluate the effects of each localized isoform, we designed peptides that specifically bind to either RI or RII. Using a peptide array, we have defined the minimal binding sequence of dual specific-AKAP 2 (d-AKAP2), which binds tightly to both RI and RII. Side-chain requirements for affinity and isoform specificity were evaluated by using a peptide substitution array where each position along the A kinase binding domain of d-AKAP2 was substituted by the other 19 l-amino acids. This array comprises 513 single-site substitution analogs of the d-AKAP2 sequence. Peptides containing single and multiple mutations were evaluated in a quantitative fluorescence binding assay and a cell-based colocalization assay. This strategy has allowed us to design peptides with high affinity (K(D) = 1-2 nM) and high specificity for RIalpha versus RIIalpha. These isoform-specific peptides will be invaluable tools to evaluate functional differences between localized RI and RII PKA and are RIalpha-specific disruptors. This array-based analysis also provides a foundation for biophysical analysis of this docking motif.
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