Different isoforms of the full-length Protein Kinase A (PKA¹) regulatory subunit homodimer (R₂) and the catalytic (C) subunit-bound holoenzyme (R₂C₂) have very different global structures despite similar molecular weights and domain organization within their primary sequences. To date, it has been the linker sequence between the R subunit dimerization/docking (D/D) domain and cAMP-binding domain A that has been implicated in modulating domain interactions to give rise to these differences in global structure. The small-angle solution scattering data presented here, for three different isoforms of PKA heterodimer ({R-C) complexes, reveal a role for another conformationally dynamic sequence in modulating inter-subunit and domain interactions; the C helix that connects the cAMP-binding domains A and B of the R subunit. The R-C heterodimer complexes studied here were each formed with a monomeric N-terminal deletion mutant of the R subunit (R) that contains the inhibitor sequence and both cAMP-binding domains. The scattering data show that type II and II R-C heterodimers are relatively compact and globular with the C subunit contacting the inhibitor sequence and both cAMP-binding domains. In contrast, the type I heterodimer is significantly more extended, with the C subunit interacting with the inhibitor sequence and cAMP-binding domain A, while domain B extends out such that its surface is almost completely solvent exposed. These data implicate the C helix of RIa in modulating isoform-specific inter-domain communication in the PKA holoenzyme, adding another layer of structural complexity to our understanding of signaling dynamics in this multi-subunit, multi-domain protein kinase.