In search of a function for the membrane anchors of class IIIa adenylate cyclases.

Nine pseudoheterodimeric mammalian adenylate cyclases possess two dissimilar hexahelical membrane domains (TM1 and TM2), two dissimilar cyclase-transducing-elements (CTEs) and two complementary catalytic domains forming a catalytic dimer (often termed cyclase-homology-domain, CHD). Canonically, these cyclases are regulated by G-proteins which are released upon ligand activation of G-protein-coupled receptors. So far, a biochemical function of the membrane domains beyond anchoring has not been established. For almost 30 years, work in our laboratory was based on the hypothesis that these voluminous membrane domains possess an additional physiological, possibly regulatory function. Over the years, we have generated numerous artificial fusion proteins between the catalytic domains of various bacterial adenylate cyclases which are active as homodimers and the membrane receptor domains of known bacterial signaling proteins such as chemotaxis receptors and quorum-sensors which have known ligands. Here we summarize the current status of our experimental efforts. Taken together, the data allow the conclusion that the hexahelical mammalian membrane anchors as well as similar membrane anchors from bacterial adenylate cyclase congeners are orphan receptors. A search for as yet unknown ligands of membrane-delimited adenylate cyclases is now warranted.