A dynamic mechanism for AKAP binding to RII isoforms of cAMP-dependent protein kinase

Mol Cell. 2006 Nov 3;24(3):397-408. doi: 10.1016/j.molcel.2006.09.015.

Abstract

A kinase-anchoring proteins (AKAPs) target PKA to specific microdomains by using an amphipathic helix that docks to N-terminal dimerization and docking (D/D) domains of PKA regulatory (R) subunits. To understand specificity, we solved the crystal structure of the helical motif from D-AKAP2, a dual-specific AKAP, bound to the RIIalpha D/D domain. The 1.6 Angstrom structure reveals how this dynamic, hydrophobic docking site is assembled. A stable, hydrophobic docking groove is formed by the helical interface of two RIIalpha protomers. The flexible N terminus of one protomer is then recruited to the site, anchored to the peptide through two essential isoleucines. The other N terminus is disordered. This asymmetry provides greater possibilities for AKAP docking. Although there is strong discrimination against RIalpha in the N terminus of the AKAP helix, the hydrophobic groove discriminates against RIIalpha. RIalpha, with a cavity in the groove, can accept a bulky tryptophan, whereas RIIalpha requires valine.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Sequence
  • Animals
  • Crystallography, X-Ray
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
  • Cyclic AMP-Dependent Protein Kinases / chemistry
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Hydrophobic and Hydrophilic Interactions
  • Isoenzymes / chemistry
  • Isoenzymes / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Proteins
  • Rats
  • Signal Transduction
  • Solutions
  • Substrate Specificity

Substances

  • Adaptor Proteins, Signal Transducing
  • Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
  • Ht 31 protein, synthetic
  • Isoenzymes
  • Prkar1a protein, rat
  • Prkar2a protein, rat
  • Proteins
  • Solutions
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases

Associated data

  • PDB/2HWN