Structure of Mycobacterium tuberculosis Cya, an evolutionary ancestor of the mammalian membrane adenylyl cyclases

Mycobacterium tuberculosis adenylyl cyclase Rv1625c / Cya is an evolutionary ancestor of the mammalian membrane adenylyl cyclases and a model system for studies of their structure and function. Although the vital role of these enzymes in cellular signaling is well established, the function of the transmembrane (TM) regions of adenylyl cyclases remains unknown. The Korkhov group determined the cryo-EM structure of Cya homodimer bound to a stabilizing nanobody at 3.6 Å resolution. The structure revealed a structurally conserved domain formed by TM helices 1-5 that facilitates the assembly of the helical and catalytic domains of the protein. The TM region contains discrete pockets accessible from the extracellular and cytosolic side of the membrane. Neutralization of the negatively charged extracellular pocket at the Cya dimer interface (site Ex1) destabilizes the cytosolic helical domain and reduces the catalytic activity of the enzyme. The TM domain acts as a functional component of Cya, guiding the assembly of the catalytic domain and providing the means for direct regulation of catalytic activity in response to extracellular ligands.

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