Intrinsic disorder in protein kinase A anchoring proteins signaling complexes

Protein kinase A (PKA) is regulated by a diverse class of anchoring proteins known as AKAPs that target PKA to subsets of its activators and substrates. Recently, it was reported that PKA can remain bound to its regulatory subunit after activation in contrast to classical model of activation-by-dissociation. This implies that PKA remains bound to the AKAPs and its substrates, and thus suggest many phosphorylation reactions occur while PKA is physically connected to its substrate. Intra-complex reactions are sensitive to the architecture of the signaling complex, but generally concentration independent. We show that most AKAPs have long intrinsically disordered regions, and suggest that they represent an adaptation for intra-complex phosphorylation. Based on polymer models of the disordered proteins, we predict that the effective concentrations of tethered substrates range from the low millimolar range to tens of micromolar. Based on recent models for intra-complex enzyme reactions, we suggest that the structure of the AKAP signaling complex is likely to be source of allosteric regulation of PKA signaling.