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Abstract:
Class III adenylate cyclases (ACs) are signaling proteins that produce the second messenger cyclic AMP (cAMP). Recently, we identified the novel cyclase transducer element (CTE) on the N-terminus of the AC catalytic domain. Biochemical characterization found the element indispensable for the regulation of AC activity in response to upstream receptor activation. Based on the ambigous coiled-coil sequence register of the CTE, we proposed a structural model in which the element acts as a hinge that switches between an experimentally observed bent conformation and a hypothetical coiled-coil conformation, thereby restricting the structural freedom of the catalytic domains to form active dimers (Fig. 1). In bacterial ACs, a CTE is present whenever the upstream signaling domain is also found in histidine kinases or similar signaling proteins, but absent when not. Thus, our data provides new insights into the evolutionary relationship between ACs and other families of signaling enzymes, as well as a structural rational for the functioning of various laboratory chimeras between them. Notably, the CTE also exists in the adenylate and guanylate cyclases of vertebrates, which are involved in many cellular signaling processes, including the propagation of signals coming from G protein-coupled receptors (GPCRs). This provides indirect evidence for a regulatory function of the membrane anchors of vertebrate ACs and suggests an additional regulatory level to GPCR signaling.
