Abstract
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 RIIalpha 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 alpha 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / metabolism*
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Amino Acid Sequence
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Animals
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Apoenzymes / metabolism
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Binding Sites
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Cattle
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Crystallography, X-Ray
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Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit
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Cyclic AMP-Dependent Protein Kinases / chemistry*
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Cyclic AMP-Dependent Protein Kinases / metabolism*
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Dimerization
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Humans
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Hydrophobic and Hydrophilic Interactions
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Mice
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Models, Molecular
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Molecular Sequence Data
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Peptides / chemistry
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Peptides / metabolism*
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Protein Binding
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Protein Structure, Secondary
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Protein Subunits / chemistry
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Protein Subunits / metabolism
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Sequence Alignment
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Substrate Specificity
Substances
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Adaptor Proteins, Signal Transducing
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Apoenzymes
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Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit
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PRKAR2A protein, human
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Peptides
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Prkar2a protein, mouse
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Protein Subunits
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Cyclic AMP-Dependent Protein Kinases
Associated data
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PDB/2IZX
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PDB/2IZY
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PDB/R2IZXSF
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PDB/R2IZYSF