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

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 RII alpha 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 RII alpha 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 RI alpha in the N terminus of the AKAP helix, the hydrophobic groove discriminates against RII alpha. Rim, with a cavity in the groove, can accept a bulky tryptophan, whereas RII alpha requires valine.