title: Defining A-Kinase Anchoring Protein (AKAP) Specificity for the Protein Kinase A Subunit RI (PKA-RI).
abstract: A-Kinase anchoring proteins (AKAPs) act as spatial and temporal regulators of protein kinase A (PKA) by localizing PKA along with multiple proteins into discrete signaling complexes. AKAPs interact with the PKA holoenzyme through an α-helix that docks into a groove formed on the dimerization/docking domain of PKA-R in an isoform-dependent fashion. In an effort to understand isoform selectivity at the molecular level, a library of protein-protein interaction (PPI) disruptors was designed to systematically probe the significance of an aromatic residue on the AKAP docking sequence for RI selectivity. The stapled peptide library was designed based on a high affinity, RI-selective disruptor of AKAP binding, RI-STAD-2. Phe, Trp and Leu were all found to maintain RI selectivity, whereas multiple intermediate-sized hydrophobic substitutions at this position either resulted in loss of isoform selectivity (Ile) or a reversal of selectivity (Val). As a limited number of RI-selective sequences are currently known, this study aids in our understanding of isoform selectivity and establishing parameters for discovering additional RI-selective AKAPs.
authors.affiliation: Dept. of Biochemistry, Universitat Kassel, Heinrich Plett Strasse 40, Kassel 34132 (Germany).
authors.forename: Karolin
authors.initials: K
authors.lastname: Autenrieth
authors.affiliation: Dept. of Pharmaceutical and Biomedical Sciences, University of Georgia, College of Pharmacy, 240 W. Green St, Athens, GA 30602 (USA).
authors.forename: N George
authors.initials: NG
authors.lastname: Bendzunas
authors.affiliation: Dept. of Biochemistry, Universitat Kassel, Heinrich Plett Strasse 40, Kassel 34132 (Germany).
authors.forename: Daniela
authors.initials: D
authors.lastname: Bertinetti
authors.affiliation: Dept. of Biochemistry, Universitat Kassel, Heinrich Plett Strasse 40, Kassel 34132 (Germany).
authors.forename: Friedrich W
authors.initials: FW
authors.lastname: Herberg
authors.affiliation: Dept. of Pharmaceutical and Biomedical Sciences, University of Georgia, College of Pharmacy, 240 W. Green St, Athens, GA 30602 (USA).
authors.forename: Eileen J
authors.initials: EJ
authors.lastname: Kennedy
mesh_terms: D054758:A Kinase Anchor Proteins / Q000737:chemistry*; D054743:Cyclic AMP-Dependent Protein Kinase Type I / Q000737:chemistry*; D019281:Dimerization; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007527:Isoenzymes / Q000737:chemistry; D062105:Molecular Docking Simulation; D011485:Protein Binding
chemical_list: D054758:A Kinase Anchor Proteins; D007527:Isoenzymes; D054743:Cyclic AMP-Dependent Protein Kinase Type I
keywords: A-kinase anchoring protein; cAMP signaling; isoforms; protein kinase A; selectivity; stapled peptides