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Class III adenylate cyclases (ACs) are widespread signaling proteins, which translate diverse intracellular and extracellular stimuli into a uniform intracellular signal. They are typically composed of an N-terminal array of sensor domains and transducers, followed C-terminally by a catalytic domain, which, after dimerization, generates the second messenger cyclic adenosine monophosphate (cAMP). Many of the N-terminal domains are also found in other signaling proteins and can frequently be recombined between them. This work bioinformatically investigates the architectural and evolutionary principles that enable the productive interaction of a great diversity of upstream regulatory domains with the conserved AC catalytic domain. As part of this process, we have identified the novel cyclase transducer element (CTE), a pivotal hinge on the N-terminus of the AC catalytic domain. The element appears to convert unspecific signals moving along the coiled-coil backbone into specific conformational changes that determine AC activity. This suggests communication along a dimeric coiled coil as the structural rationale for the architectural similarities between many families of signaling proteins. Further, we bioinformatically classify the various six-helical transmembrane (6TM) domains observed in many bacterial and eukaryotic ACs. Recently, experimental results have indicated that these domains could function as regulatory receptors binding hydrophobic ligands inside the membrane. Our classification and the presence of a CTE in many 6TM ACs strongly support this hypothesis, concluding that some or all 6TM domains are regulatory receptors for as-yet-unknown ligands. Since mammalian ACs are important downstream messengers of G protein-coupled receptors, these findings suggest AC 6TM domains could be drug targets of possibly great pharmacological relevance.