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PaExoY is composed of a smaller actin-binding domain (ABD) that is connected via a hydrophobic core (Supplementary Fig. 2a) with a 2.7 Å root-mean-square deviation (RMSD) between all common atoms. 1b and c) is similar to the structure of PaExoY in the apo state 22 (Supplementary Fig. The overall structure of PaExoY bound to F-actin (Fig. Thus, this mechanism appears to be general for both bacterial cyclase toxin families. Our structural data together with molecular dynamics simulations and enzymatic assays reveal that specific interactions between two independent regions of the toxins with F-, or G-actin lead to stabilization of the catalytic center of the toxins and high enzymatic activity. Here we report cryo-EM structures of PaExoY and VvExoY in complex with their activators F-actin and G-actin-profilin.
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However, it is not known if activation of nucleotidyl cyclases by actin follows the same molecular mechanism.
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A series of structural studies revealed that interaction with calmodulin promotes a disordered-to-ordered transition in the catalytic center that is necessary for the efficient catalysis 16, 17, 18. A similar activation potency was observed in other members of nucleotidyl cyclase family, such as the edema factor of Bacillus anthracis and the adenylate cyclase domain of CyaA of Bordetella pertussis, which are activated by calmodulin. However, once delivered into the target eukaryotic cell, the effectors bind to actin, resulting in more than 10,000-fold increase in nucleotidyl cyclase activity 15. These large toxins combine toxic effector modules with their delivery apparatus in a single polypeptide chain 14.īoth PaExoY and VvExoY are catalytically inactive inside bacteria.
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In contrast to PaExoY, VvExoY and VnExoY are not delivered by T3SS but as modules of MARTX (Multifunctional-Autoprocessing Repeats-in-ToXin). VvExoY is essential for virulence in mice and is responsible for severe tissue damage 13.
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nigripulchritudo also possess ExoY-like toxins (VvExoY and VnExoY, respectively), which act as adenylate cyclases 12. A recent report has established a link between the presence of PaExoY in clinical isolates and end-organ dysfunction in critically ill patients 11. aeruginosa to hijack host immune response by a suppression of TAK1 and a decreased production of interleukin 1 9, 10. At lower PaExoY concentrations, which are more likely to occur during chronical infection, the activity of PaExoY allows P. At high concentrations, this results in the death of the intoxicated cultured cells 7, 8. It produces a supraphysiologic amount of 3′,5′-cyclic guanosine monophosphate (cGMP) and 3′,5′-cyclic adenosine monophosphate (cAMP) and thereby disorganizes cell signaling 6. One of such T3SS effectors is the nucleotidyl cyclase toxin exoenzyme Y (PaExoY) 5. aeruginosa is the type 3 secretion system (T3SS), a cell wall associated nanomachine which transports a panel of effectors into eukaryotic target cells 3, 4. Pseudomonas aeruginosa and Vibrio vulnificus are human pathogens that cause nosocomial infections and seafood-related illnesses, respectively, with severity ranging from benign and local to systemic and life-threatening 1, 2. Other nucleotidyl cyclase toxins that bind to calmodulin rather than actin undergo a similar disordered-to-ordered transition during activation, suggesting that the allosteric activation-by-stabilization mechanism of ExoY is conserved in these enzymes, albeit the different activator. Differences in the sequence and conformation of the actin-binding regions are responsible for the selective binding to either F- or G-actin. The specific stabilization of these regions results in an allosteric stabilization of the nucleotide binding pocket and thereby to an activation of the enzyme. The structures reveal that in contrast to the apo-state, two flexible regions become ordered and interact strongly with actin. Here, we report structures of ExoY from Pseudomonas aeruginosa and Vibrio vulnificus bound to their corresponding activators F-actin and profilin-G-actin. The underlying molecular mechanism of this activation is, however, unclear. Bacterial human pathogens secrete initially inactive nucleotidyl cyclases that become potent enzymes by binding to actin inside eukaryotic host cells.