Structure of adenylyl cyclase 5 in complex with G¦ offers insights into ADCY5-related dyskinesia

The nine different membrane-anchored adenylyl cyclase isoforms (AC1-9) in mammals are stimulated by the heterotrimeric G protein, G alpha(s), but their response to G beta gamma regulation is isoform specific. In the present study, we report cryo-electron microscope structures of ligand-free AC5 in complex with G beta gamma and a dimeric form of AC5 that could be involved in its regulation. G beta gamma binds to a coiled-coil domain that links the AC transmembrane region to its catalytic core as well as to a region (C-1b) that is known to be a hub for isoform-specific regulation. We confirmed the G beta gamma interaction with both purified proteins and cell-based assays. Gain-of-function mutations in AC5 associated with human familial dyskinesia are located at the interface of AC5 with G beta gamma and show reduced conditional activation by G beta gamma, emphasizing the importance of the observed interaction for motor function in humans. We propose a molecular mechanism wherein G beta gamma either prevents dimerization of AC5 or allosterically modulates the coiled-coil domain, and hence the catalytic core. As our mechanistic understanding of how individual AC isoforms are uniquely regulated is limited, studies such as this may provide new avenues for isoform-specific drug development.