1. Molecular Basis of AKAP Specificity for PKA Regulatory Subunits
- Author
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Kjetil Taskén, Pawel Dokurno, Birgitte Lygren, Matthew G. Gold, Naoto Hoshi, Cathrine Rein Carlson, John D. Scott, David Barford, and George McConnachie
- Subjects
Models, Molecular ,Gene isoform ,A-kinase-anchoring protein ,endocrine system ,Protein subunit ,Molecular Sequence Data ,Peptide ,Biology ,Crystallography, X-Ray ,Protein Structure, Secondary ,Substrate Specificity ,A Kinase Anchor Proteins ,Mice ,Apoenzymes ,Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit ,Animals ,Humans ,Amino Acid Sequence ,Protein kinase A ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,chemistry.chemical_classification ,Binding Sites ,Cell Biology ,Cyclic AMP-Dependent Protein Kinases ,Protein Subunits ,chemistry ,Structural biology ,Biochemistry ,Docking (molecular) ,Biophysics ,Cattle ,Peptides ,Dimerization ,Hydrophobic and Hydrophilic Interactions ,Sequence Alignment ,Protein Binding - Abstract
Summary Localization of cyclic AMP (cAMP)-dependent protein kinase (PKA) by A kinase-anchoring proteins (AKAPs) restricts the action of this broad specificity kinase. The high-resolution crystal structures of the docking and dimerization (D/D) domain of the RIIα regulatory subunit of PKA both in the apo state and in complex with the high-affinity anchoring peptide AKAP- IS explain the molecular basis for AKAP-regulatory subunit recognition. AKAP- IS folds into an amphipathic α helix that engages an essentially preformed shallow groove on the surface of the RII dimer D/D domains. Conserved AKAP aliphatic residues dominate interactions to RII at the predominantly hydrophobic interface, whereas polar residues are important in conferring R subunit isoform specificity. Using a peptide screening approach, we have developed SuperAKAP- IS , a peptide that is 10,000-fold more selective for the RII isoform relative to RI and can be used to assess the impact of PKA isoform-selective anchoring on cAMP-responsive events inside cells.
- Published
- 2006