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Defining A‐Kinase Anchoring Protein (AKAP) Specificity for the Protein Kinase A Subunit RI (PKA‐RI)
Author(s) -
Autenrieth Karolin,
Bendzunas N. George,
Bertinetti Daniela,
Herberg Friedrich W.,
Kennedy Eileen J.
Publication year - 2016
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201500632
Subject(s) - gene isoform , docking (animal) , selectivity , protein kinase a , protein subunit , chemistry , peptide , biochemistry , kinase , biophysics , biology , gene , medicine , nursing , catalysis
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.