Phage dUTPases Control Transfer of Virulence Genes by a Proto-Oncogenic G Protein-like Mechanism

• Published in: Molecular cell 2013-03, Vol.49 (5), p.947-958
• Main Authors: Tormo-Más, María Ángeles, Donderis, Jorge, García-Caballer, María, Alt, Aaron, Mir-Sanchis, Ignacio, Marina, Alberto, Penadés, José R.
• Format: Article
• Language: English
• Subjects: bacteriophages; Binding Sites; Derepression; genes; Genomic Islands - genetics; GTP-Binding Proteins - genetics; GTP-Binding Proteins - metabolism; hydrolysis; Models, Molecular; mutagenicity; pathogenicity islands; Protein Structure, Tertiary; proteins; Pyrophosphatases - genetics; Pyrophosphatases - metabolism; Staphylococcus aureus - genetics; Staphylococcus aureus - metabolism; Staphylococcus aureus - pathogenicity; Substrate Specificity; Viral Proteins - genetics; Viral Proteins - metabolism; virulence; Virulence - genetics
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2012.12.013

dUTPases (Duts) have emerged as promising regulatory molecules controlling relevant cellular processes. However, the mechanism underlying this regulatory function remains enigmatic. Using staphylococcal pathogenicity island (SaPI) repression as a model, we report here that phage Duts induce the transfer of SaPI-encoded virulence factors by switching between active (dUTP-bound) and inactive (apo state) conformations, a conversion catalyzed by their intrinsic dUTPase activity. Crystallographic and mutagenic analyses demonstrate that binding to dUTP reorders the C-terminal motif V of the phage-encoded Duts, rendering these proteins into the active conformation required for SaPI derepression. By contrast, the conversion to the apo state conformation by hydrolysis of the bound dUTP generates a protein that is unable to induce the SaPI cycle. Because none of the requirements involving Duts in SaPI transfer are exclusive to the phage-encoded proteins, we propose that Duts are widespread cellular regulators acting in a manner analogous to the eukaryotic G proteins. [Display omitted] ► dUTPases are signaling molecules acting in analogous manner to the G proteins ► Binding to dUTP induces a conformational change in the phage-encoded dUTPases ► The dUTP-bound form of the phage dUTPases induces transfer of virulence genes ► The dUTPase P loop-like motif V is the molecular switch of the signaling mechanism