The bacteriophage–phage-inducible chromosomal island arms race designs an interkingdom inhibitor of dUTPases

DOI: 10.1128/spectrum.03232-22

Authors: Carla Sanz-Frasquet (CSIC and CIBER de Enfermedades Raras (CIBERER)) , J. Rafael Ciges-Tomas (CSIC and CIBER de Enfermedades Raras (CIBERER)) , Christian Alite (CSIC and CIBER de Enfermedades Raras (CIBERER)) , José R. Penadés (University of Glasgow; Imperial College London) , Alberto Marina (CSIC and CIBER de Enfermedades Raras (CIBERER))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Microbiology Spectrum

State: Published (Approved)
Published: January 2023
Diamond Proposal Number(s): 28394

Abstract: Stl, the master repressor of the Staphylococcus aureus pathogenicity islands (SaPIs), targets phage-encoded proteins to derepress and synchronize the SaPI and the helper phage life cycles. To activate their cycle, some SaPI Stls target both phage dimeric and phage trimeric dUTPases (Duts) as antirepressors, which are structurally unrelated proteins that perform identical functions for the phage. This intimate link between the SaPI’s repressor and the phage inducer has imposed an evolutionary optimization of Stl that allows the interaction with Duts from unrelated organisms. In this work, we structurally characterize this sophisticated mechanism of specialization by solving the structure of the prototypical SaPIbov1 Stl in complex with a prokaryotic and a eukaryotic trimeric Dut. The heterocomplexes with Mycobacterium tuberculosis and Homo sapiens Duts show the molecular strategy of Stl to target trimeric Duts from different kingdoms. Our structural results confirm the participation of the five catalytic motifs of trimeric Duts in Stl binding, including the C-terminal flexible motif V that increases the affinity by embracing Stl. In silico and in vitro analyses with a monomeric Dut support the capacity of Stl to recognize this third family of Duts, confirming this protein as a universal Dut inhibitor in the different kingdoms of life.

Diamond Keywords: Bacteriophages; Viruses

Subject Areas: Biology and Bio-materials


Instruments: I24-Microfocus Macromolecular Crystallography

Other Facilities: XALOC at ALBA; ESRF

Added On: 23/01/2023 09:10

Documents:
spectrum.03232-22.pdf

Discipline Tags:

Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)