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Streptococcus pyogenes nuclease A interferes with host complement functions

A. Bennig, Isabella LU orcid ; Ströbaek, Joel LU ; Mamede, Rafael ; Neumann, Ariane LU orcid ; Friães, Ana ; Ramirez, Mario ; Hall, Michael ; Collin, Mattias LU orcid ; Malmström, Lars LU and Ekström, Simon LU , et al. (2025) p.1-16
Abstract
Bacterial pathogens deploy diverse virulence factors to subvert host immunity, yet the molecular details of these interactions often remain unresolved. Here, we investigate the structure and host interactome of the Streptococcus pyogenes nuclease A (SpnA). We characterized the structure and dynamics of SpnA using hydrogen-deuterium exchange mass spectrometry and single-particle electron cryo microscopy, yielding the first structural insights to this protein. This allowed us to identify an additional oligonucleotide-binding domain whose flexible structure may play an important function in the nucleolytic activity of SpnA. Affinity-pulldown mass spectrometry identified the complement system membrane attack complex C5b67 components as key... (More)
Bacterial pathogens deploy diverse virulence factors to subvert host immunity, yet the molecular details of these interactions often remain unresolved. Here, we investigate the structure and host interactome of the Streptococcus pyogenes nuclease A (SpnA). We characterized the structure and dynamics of SpnA using hydrogen-deuterium exchange mass spectrometry and single-particle electron cryo microscopy, yielding the first structural insights to this protein. This allowed us to identify an additional oligonucleotide-binding domain whose flexible structure may play an important function in the nucleolytic activity of SpnA. Affinity-pulldown mass spectrometry identified the complement system membrane attack complex C5b67 components as key interactors in human plasma. Cross-linking mass spectrometry combined with integrative modeling identified the direct binding interfaces between SpnA and C5b67. These interfaces are highly conserved among genetically diverse S. pyogenes strains. The interaction between SpnA and C5b67 is suggested to prevent the assembly of a functional membrane attack complex. Taken together, our findings uncover a novel function of SpnA in complement inhibition and identifies new potential targets to prevent and treat S. pyogenes infections. (Less)
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organization
publishing date
type
Working paper/Preprint
publication status
published
subject
pages
1 - 16
publisher
bioRxiv
DOI
10.1101/2025.08.25.672074
language
English
LU publication?
yes
id
3848430c-9369-4249-b5d9-b73bfbf386a0
date added to LUP
2025-11-18 09:15:42
date last changed
2025-11-18 14:05:34
@misc{3848430c-9369-4249-b5d9-b73bfbf386a0,
  abstract     = {{Bacterial pathogens deploy diverse virulence factors to subvert host immunity, yet the molecular details of these interactions often remain unresolved. Here, we investigate the structure and host interactome of the Streptococcus pyogenes nuclease A (SpnA). We characterized the structure and dynamics of SpnA using hydrogen-deuterium exchange mass spectrometry and single-particle electron cryo microscopy, yielding the first structural insights to this protein. This allowed us to identify an additional oligonucleotide-binding domain whose flexible structure may play an important function in the nucleolytic activity of SpnA. Affinity-pulldown mass spectrometry identified the complement system membrane attack complex C5b67 components as key interactors in human plasma. Cross-linking mass spectrometry combined with integrative modeling identified the direct binding interfaces between SpnA and C5b67. These interfaces are highly conserved among genetically diverse S. pyogenes strains. The interaction between SpnA and C5b67 is suggested to prevent the assembly of a functional membrane attack complex. Taken together, our findings uncover a novel function of SpnA in complement inhibition and identifies new potential targets to prevent and treat S. pyogenes infections.}},
  author       = {{A. Bennig, Isabella and Ströbaek, Joel and Mamede, Rafael and Neumann, Ariane and Friães, Ana and Ramirez, Mario and Hall, Michael and Collin, Mattias and Malmström, Lars and Ekström, Simon and Frick, Inga-Maria and Björck, Lars and Happonen, Lotta J.}},
  language     = {{eng}},
  month        = {{08}},
  note         = {{Preprint}},
  pages        = {{1--16}},
  publisher    = {{bioRxiv}},
  title        = {{Streptococcus pyogenes nuclease A interferes with host complement functions}},
  url          = {{http://dx.doi.org/10.1101/2025.08.25.672074}},
  doi          = {{10.1101/2025.08.25.672074}},
  year         = {{2025}},
}