Unknown

Dataset Information

0

Investigating PKA-RII specificity using analogs of the PKA:AKAP peptide inhibitor STAD-2.


ABSTRACT: Generation of the second messenger molecule cAMP mediates a variety of cellular responses which are essential for critical cellular processes. In response to elevated cAMP levels, cAMP dependent protein kinase (PKA) phosphorylates serine and threonine residues on a wide variety of target substrates. In order to enhance the precision and directionality of these signaling events, PKA is localized to discrete locations within the cell by A-kinase anchoring proteins (AKAPs). The interaction between PKA and AKAPs is mediated via an amphipathic ?-helix derived from AKAPs which binds to a stable hydrophobic groove formed in the dimerization/docking (D/D) domain of PKA-R in an isoform-specific fashion. Although numerous AKAP disruptors have previously been identified that can inhibit either RI- or RII-selective AKAPs, no AKAP disruptors have been identified that have isoform specificity for RI? versus RI? or RII? versus RII?. As a strategy to identify isoform-specific AKAP inhibitors, a library of chemically stapled protein-protein interaction (PPI) disruptors was developed based on the RII-selective AKAP disruptor, STAD-2. An alanine was substituted at each position in the sequence, and from this library it was possible to delineate the importance of longer aliphatic residues in the formation of a region which complements the hydrophobic cleft formed by the D/D domain. Interestingly, lysine residues that were added to both terminal ends of the peptide sequence to facilitate water solubility appear to contribute to isoform specificity for RII? over RII? while having only weak interaction with RI. This work supports current hypotheses on the mechanisms of AKAP binding and highlights the significance of particular residue positions that aid in distinguishing between the RII isoforms and may provide insight into future design of isoform-selective AKAP disruptors.

SUBMITTER: Bendzunas NG 

PROVIDER: S-EPMC5844854 | BioStudies | 2018-01-01

REPOSITORIES: biostudies

Similar Datasets

2015-01-01 | S-EPMC4475429 | BioStudies
2014-01-01 | S-EPMC3985448 | BioStudies
2006-01-01 | S-EPMC1698590 | BioStudies
2012-01-01 | S-EPMC3527963 | BioStudies
2016-01-01 | S-EPMC4836982 | BioStudies
2016-01-01 | S-EPMC4964276 | BioStudies
2003-01-01 | S-EPMC153575 | BioStudies
2008-01-01 | S-EPMC2522378 | BioStudies
1000-01-01 | S-EPMC2689760 | BioStudies
1000-01-01 | S-EPMC3058957 | BioStudies