Defining A‐Kinase Anchoring Protein (AKAP) Specificity for the Protein Kinase A Subunit RI (PKA‐RI). (17th December 2015)

• Record Type: Journal Article
• Authors: Autenrieth, Karolin; Bendzunas, N. George; Bertinetti, Daniela; Herberg, Friedrich W.; Kennedy, Eileen J.
• Is Part Of: Chembiochem. Volume 17:Number 8(2016)
• Page Start: 693
• Page End: 697
• Publication Date: 2015-12-17
• Subjects: A-kinase anchoring protein -- cAMP signaling -- isoforms -- protein kinase A -- selectivity -- stapled peptides; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201500632
• Languages: English
• ISSNs: 1439-4227

Abstract

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. Abstract : Defining a docking target : AKAP docking sequences bind PKA‐R in an isoform‐specific manner; however, it remains unclear how isoform specificity is defined. Analysis of a stapled peptide library of sequences aids in our understanding of how AKAP sequence variance leads to isoform selectivity and might establish parameters for discovering additional RI‐selective AKAPs.