The chilling of adenylyl cyclase 9 and its translational potential

• Published in: Cellular signalling 2020-06, Vol.70, p.109589-109589, Article 109589
• Main Author: Antoni, Ferenc A.
• Format: Article
• Language: English
• Subjects: Autoinhibition; Cyclic AMP; Genome-wide association screen; Paralogue-specific regulation; Transmembrane adenylyl cyclase
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2020.109589

A recent break-through paper has revealed for the first time the high-resolution, three-dimensional structure of a mammalian trans-membrane adenylyl cyclase (tmAC) obtained by cryo-electronmicroscopy (cryo-EM). Reporting the structure of adenylyl cyclase 9 (AC9) in complex with activated Gsα, the cryo-EM study revealed that AC9 has three functionally interlinked, yet structurally distinct domains. The array of the twelve transmembrane helices is connected to the cytosolic catalytic core by two helical segments that are stabilized through the formation of a parallel coiled-coil. Surprisingly, in the presence of Gsα, the isoform-specific carboxyl-terminal tail of AC9 occludes the forskolin- as well as the active substrate-sites, resulting in marked autoinhibition of the enzyme. As AC9 has the lowest primary sequence homology with the eight further mammalian tmAC paralogues, it appears to be the best candidate for selective pharmacologic targeting. This is now closer to reality as the structural insight provided by the cryo-EM study indicates that all of the three structural domains are potential targets for bioactive agents. The present paper summarizes for molecular physiologists and pharmacologists what is known about the biological role of AC9, considers the potential modes of physiologic regulation, as well as pharmacologic targeting on the basis of the high-resolution cryo-EM structure. The translational potential of AC9 is considered upon highlighting the current state of genome-wide association screens, and the corresponding experimental evidence. Overall, whilst the high- resolution structure presents unique opportunities for the full understanding of the control of AC9, the data on the biological role of the enzyme and its translational potential are far from complete, and require extensive further study.