Molecular basis of AKAP specificity for PKA regulatory subunits

Mol Cell. 2006 Nov 3;24(3):383-95. doi: 10.1016/j.molcel.2006.09.006.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Sequence
  • Animals
  • Apoenzymes / metabolism
  • Binding Sites
  • Cattle
  • Crystallography, X-Ray
  • Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit
  • Cyclic AMP-Dependent Protein Kinases / chemistry*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Dimerization
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Peptides / chemistry
  • Peptides / metabolism*
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism
  • Sequence Alignment
  • Substrate Specificity

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoenzymes
  • Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit
  • PRKAR2A protein, human
  • Peptides
  • Prkar2a protein, mouse
  • Protein Subunits
  • Cyclic AMP-Dependent Protein Kinases

Associated data

  • PDB/2IZX
  • PDB/2IZY
  • PDB/R2IZXSF
  • PDB/R2IZYSF