Defining A-Kinase Anchoring Protein (AKAP) Specificity for the Protein KinaseA Subunit RI (PKA-RI)

被引：13

作者：

Autenrieth, Karolin ^{[2
]}

Bendzunas, N. George ^{[1
]}

Bertinetti, Daniela ^{[2
]}

Herberg, Friedrich W. ^{[2
]}

Kennedy, Eileen J. ^{[1
]}

机构：

[1] Univ Georgia, Coll Pharm, Dept Pharmaceut & Biomed Sci, 240 W Green St, Athens, GA 30602 USA

[2] Univ Kassel, Dept Biochem, Heinrich Plett Str 40, D-34132 Kassel, Germany

来源：

CHEMBIOCHEM | 2016年 / 17卷 / 08期

基金：

美国国家卫生研究院;

关键词：

A-kinase anchoring protein; cAMP signaling; isoforms; protein kinaseA; selectivity; stapled peptides; REGULATORY SUBUNITS; SELECTIVE DISRUPTION; PEPTIDE DISRUPTORS; COMPLEXES; BINDING; MOTIFS;

D O I：

10.1002/cbic.201500632

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A-Kinase anchoring proteins (AKAPs) act as spatial and temporal regulators of protein kinaseA (PKA) by localizing PKA along with multiple proteins into discrete signaling complexes. AKAPs interact with the PKA holoenzyme through an alpha-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.

引用

页码：693 / 697

页数：5

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