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Significance Protein kinase A, containing a dimeric regulatory (R)-subunit and 2 catalytic (C)-subunits, is the primary driver of cAMP signaling. The 4 R-subunits (RIα, RIβ, RIIα, RIIβ) form R2 C2 holoenzymes with distinct functions. Our 2 RIα holoenzyme states, reflecting the presence and absence of ATP, not only reveal isoform-specific quaternary differences but also provide new insights into understanding of the role of ATP. Combined with biochemical and biophysical analyses, plus molecular dynamics simulations, we show how ATP functions in RIα holoenzymes as an inhibitor that competes with the allosteric activator, cAMP. This is distinct from the RIIβ holoenzyme, where different interfaces lead to distinct allosteric signaling networks. These isoform-specific differences contribute significantly to the combinatorial diversity of PKA signaling in cells.

Two PKA RIα holoenzyme states define ATP as an isoform-specific orthosteric inhibitor that competes with the allosteric activator, cAMP