Structural basis of activation and inhibition of the Ca2+/calmodulin-sensitive adenylyl cyclase 8 (LiP-MS)

Membrane adenylyl cyclases (ACs) catalyze the conversion of ATP to cAMP, a second messenger involved in different signaling pathways. AC8 is one of the 9 membrane-bound isoforms, present in the brain and implicated in cognitive functions. AC8 is regulated by Ca2+/CaM and different G proteins but structural evidence on its regulation is scarce. We solved the structure of full-length AC8 in complex with Gas and CaM. ACs contain large stretches of disordered/highly flexible domains that cannot be resolved with cryo-EM. To overcome this limitation, we have studied AC8's interaction with Gas and Gbg using limited proteolysis-coupled mass spectrometry (LiP-MS). A previously published data set on the interaction of AC8 and CaM was included in the analysis (PXD039520).