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Heparin promotes fibrillation of most phenol soluble modulin virulence peptides from S. aureus

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  • Zahra Najarzadeh, Interdisciplinary Nanoscience Centre (INANO)
  • ,
  • Masihuz Zaman, Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus University, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • ,
  • Vita Sereikaite, 1Copenhagen University Hospital, Copenhagen, Denmark. 2Aarhus University Hospital, Aarhus, Denmark. 3University of Copenhagen, Copenhagen, Denmark. 4Odense University Hospital, Odense, Denmark.
  • ,
  • Kristian Strømgaard, Department of Drug Design and Pharmacology, University of Copenhagen, Denmark, 1Copenhagen University Hospital, Copenhagen, Denmark. 2Aarhus University Hospital, Aarhus, Denmark. 3University of Copenhagen, Copenhagen, Denmark. 4Odense University Hospital, Odense, Denmark.
  • ,
  • Maria Andreasen
  • Daniel E Otzen

Phenol-soluble modulins (PSMs) such as α-PSMs, β-PSMs, and δ-toxin are virulence peptides secreted by different Staphylococcus aureus strains. PSMs are able to form amyloid fibrils, which may strengthen the biofilm matrix that promotes bacterial colonization of and extended growth on surfaces (e.g. cell tissue) and increases antibiotic resistance. Many components contribute to biofilm formation, including the human-produced highly-sulfated glycosaminoglycan heparin. Although heparin promotes S.aureus infection, the molecular basis for this is unclear. Given that heparin is known to induce fibrillation of a wide range of proteins, we hypothesized that heparin aids bacterial colonization by promoting PSM fibrillation. Here we address this hypothesis using a combination of Thioflavin T-fluorescence kinetic studies, circular dichroism, FTIR, electron microscopy and peptide microarrays to investigate the mechanism of aggregation, the structure of the fibrils and identify possible binding regions. We found that heparin accelerates fibrillation of all α-PSMs (except PSMα2) and δ-toxin, but inhibits β-PSM fibrillation by blocking nucleation or reducing fibrillation levels. Given that S. aureus secretes higher levels of α-PSM than β-PSM peptides, heparin is therefore likely to promote fibrillation overall. Heparin binding is driven by multiple positively charged lysine residues in α-PSMs and δ-toxins, the removal of which strongly reduced binding affinity. Binding of heparin did not affect the structure of the resulting fibrils, i.e. the outcome of the aggregation process. Rather, heparin provided a scaffold to catalyze or inhibit fibrillation. Based on our findings, we speculate that heparin may strengthen the bacterial biofilm and therefore enhance colonization via increased PSM fibrillation.

Original languageEnglish
JournalThe Journal of Biological Chemistry
Pages (from-to)100953
ISSN0021-9258
DOIs
Publication statusE-pub ahead of print - 13 Jul 2021

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Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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