The structure of a membrane adenylyl cyclase bound to an activated stimulatory G protein
Membrane adenylyl cyclases (ACs) are the key enzymes in cellular signaling, producing second messenger cAMP in response to a variety cues. A recent paper in Science by the Korkhov group (IBC & PSI) describes the first structure of a full-length membrane AC, providing new insights into its mechanism.
The structure of AC9 bound to an activated G protein s subunit, solved at a resolution of 3.4 Å by cryo-EM and single particle analysis, reveals the organization of a complete AC-G protein complex. The structure features the key domains of the membrane AC: the membrane domain, the cytosolic catalytic domain, and the helical domain that connects the membrane and the catalytic portions of AC9. The structure also features a C-terminal peptide occluding the catalytic and allosteric sites of AC9. The occluded state of the AC is distinct from its substrate- and activator-bound state. The structural and biochemical evidence provides new insights into the auto-regulatory function of the C-terminus. The natural ligand for the AC allosteric site has until now remained unknown, and thus the results hint at the potential physiological role of the allosteric site of the membrane ACs in direct protein-protein interactions. Similar modes of regulation may apply to other membrane ACs.
Link to the paper in "Science"