Adenylyl Cyclase 9: A Maverick Signalling Act in Search of Plots

Cryo-electronmicroscopy has revolutionized the study of integral membrane proteins. In the case of adenylyl cyclase 9 (AC9)—one of nine transmembrane paralogues in mammals that produce the ubiquitous intracellular messenger cyclic AMP—the technique was instrumental in revealing the structural basis of a biological paradox, namely, that AC9 is strongly autoinhibited when in a complex with its physiological stimulus, receptor-activated Gsα. Furthermore, AC9 is also insensitive to inhibitory G proteins because it lacks the requisite binding pocket. As AC9 is widely distributed in the body, this regulatory conundrum has potentially broad implications. However, deletion of the adcy9 gene in mice causes a high level of pre-weaning lethality. Hence, our knowledge regarding the biological role of AC9 in mammals is rudimentary at best. In mammalian AC9, autoinhibition is modulated by post-translational modifications, including protein phosphorylation. However, AC9 has over 70 documented phosphorylations, the majority of them on serines in isoform-specific disordered domains. What is their functional relevance—if any? This paper reviews the current knowledge regarding the regulation of AC9, a maverick amongst transmembrane adenylyl cyclases.