TY - JOUR T1 - Structure of <em>Mycobacterium tuberculosis</em> Cya, an evolutionary ancestor of the mammalian membrane adenylyl cyclases JF - bioRxiv DO - 10.1101/2021.12.01.470738 SP - 2021.12.01.470738 AU - Ved Mehta AU - Basavraj Khanppnavar AU - Dina Schuster AU - Ilayda Kantarci AU - Irene Vercellino AU - Angela Kosturanova AU - Tarun Iype AU - Sasa Stefanic AU - Paola Picotti AU - Volodymyr M. Korkhov Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/01/13/2021.12.01.470738.abstract N2 - Mycobacterium tuberculosis adenylyl cyclase (AC) Rv1625c / Cya is an evolutionary ancestor of the mammalian membrane ACs and a model system for studies of their structure and function. Although the vital role of ACs in cellular signaling is well established, the function of their transmembrane (TM) regions remains unknown. Here we describe the cryo-EM structure of Cya bound to a stabilizing nanobody at 3.6 Å resolution. The TM helices 1-5 form a structurally conserved domain that facilitates the assembly of the helical and catalytic domains. The TM region contains discrete pockets accessible from the extracellular and cytosolic side of the membrane. Neutralization of the negatively charged extracellular pocket 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.One-Sentence Summary Structure of M. tuberculosis membrane adenylyl cyclase CyaCompeting Interest StatementThe authors have declared no competing interest. ER -