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Cited by 0Bacteriophages and microbial interactionsStreptococcal Infections and TreatmentsBacterial Genetics and Biotechnology

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The phage protein paratox is a multifunctional metabolic regulator of Streptococcus

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Muna, Tasneem Hassan, Rutbeek, Nicole R, Horne, Julia, Lao, Ying W, Krokhin, Oleg V, Prehna, Gerd·2025·Nucleic Acids Research
DOI 10.1093/nar/gkae1200PMC PMC11754733

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Abstract

Streptococcus pyogenes, or Group A Streptococcus (GAS), is a commensal bacteria and human pathogen. Central to GAS pathogenesis is the presence of prophage encoded virulence genes. The conserved phage gene for the protein paratox (Prx) is genetically linked to virulence genes, but the reason for this linkage is unknown. Prx inhibits GAS quorum sensing and natural competence by binding the transcription factor ComR. However, inhibiting ComR does not explain the virulence gene linkage. To address this, we took a mass spectrometry approach to search for other Prx interaction partners. The data demonstrates that Prx binds numerous DNA-binding proteins and transcriptional regulators. We show binding of Prx in vitro with the GAS protein Esub1 (SpyM3_0890) and the phage protein JM3 (SpyM3_1246). An Esub1:Prx complex X-ray crystal structure reveals that Esub1 and ComR possess a conserved Prx-binding helix. Computational modelling predicts that the Prx-binding helix is present in several, but not all, binding partners. Namely, JM3 lacks the Prx-binding helix. As Prx is conformationally dynamic, this suggests partner-dependent binding modes. Overall, Prx acts as a metabolic regulator of GAS to maintain the phage genome. As such, Prx maybe a direct contributor to the pathogenic conversion of GAS.

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Metadata

Authors
Muna, T. H., Rutbeek, N. R., Horne, J., Lao, Y. W., Krokhin, O. V., & Prehna, G.
Affiliations
University of Manitoba (CA)
Corresponding author
Prehna, Gerd
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2024-12-14
Volume
53
Issue
2
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
DOI
10.1093/nar/gkae1200
PMC
PMC11754733
OpenAlex
W4405393663
Cited by
0
References
1
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Nucleic Acids Research (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • Natural Sciences and Engineering Research Council of Canada (RGPIN-2018-04968)
  • Manitoba Medical Service Foundation (8-2020-10)
  • Canadian Foundation for Innovation (37841)
  • University of Manitoba
  • NSERC (RGPIN-2022-05015)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › Bacteriophages and microbial interactions
  • Health Sciences › Medicine › Infectious Diseases › Streptococcal Infections and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Keywords
Streptococcus pyogenes, prophages, metabolic regulation, quorum sensing, natural competence, protein-protein interaction
MeSH terms
Bacterial Proteins, Binding Sites, DNA-Binding Proteins, Models, Molecular, Protein Binding, Streptococcus pyogenes, Transcription Factors, Viral Proteins, Gene Expression Regulation, Bacterial, Streptococcus Phages, Crystallography, X-Ray

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