Human Fibrinogen Inhibits Amyloid Assembly of Most Phenol-Soluble Modulins from Staphylococcus aureus

Abstract

Functional amyloids are highly organized protein/peptide structures that inter alia promote biofilm formation in different bacteria. One such example is provided by a family of 20–45 residue-long peptides called phenol-soluble modulins (PSMs) from Staphylococcus aureus . External components such as eukaryotic host proteins, which alter self-assembly of bacterial amyloids, can affect the biofilm matrix. Here, we studied the effect of the highly prevalent human plasma protein fibrinogen (Fg) on fibrillation of PSMs. Fg inhibits or suppresses fibrillation of most PSMs tested (PSMα1, PSMβ1, and PSMβ2) except for PSMα3, whose already rapid aggregation is accelerated even further by Fg but leads to amorphous β-rich aggregates rather than fibrils. Fg also induces PSMβ2 to form amorphous aggregates and diverts PSMα1 into off-pathway oligomers which consist of both Fg and PSMα1 and cannot seed fibrillation. Peptide arrays showed that Fg bound to the N-terminus of PSMα1, while it bound to the entire length of PSMα3 (except the C terminus) and to the C-termini of PSMβ1 and PSMβ2. The latter peptides are all positively charged, while Fg is negatively charged at physiological pH. The positive charges complement Fg’s net negative charge of −7.6 at pH 7.4. Fg’s ability to inhibit PSM fibrillation reveals a potential host-defense mechanism to prevent bacterial biofilm growth and infections in the human body.

Staphylococcus aureusDelta Toxin Modulates both Extracellular Membrane Vesicle Biogenesis and Amyloid Formation

“…Although δ-toxin was the most abundant PSM in lavage fluids, host-derived factors could impede fibril formation in vivo. Najarzadeh et al reported that human plasma fibrinogen inhibits fibrillation of PSMα1, PSMβ1, and PSMβ2 and induces fibrillation in PSMα3, but its impact on δ-toxin fibrillation was not investigated (61). Serum lipoproteins have been shown to bind to and neutralize the biologic activities of PSMs (62).…”

Antibiofilm mechanism of a novel milk-derived antimicrobial peptide against Staphylococcus aureus by downregulating agr quorum sensing system

“…Additionally, it has been proved that the effect of agr QS system on biofilm depends on the surfactant properties of the toxin (Yarwood & Schlievert, 2003). The phenol‐soluble modulins (PSMs) are a type of surfactant and are responsible for regulating biofilm formation (Najarzadeh et al, 2021). In this study, the protein psmβ related to the agr system was downregulated.…”

Interaction of Membrane Vesicles with the Pseudomonas Functional Amyloid Protein FapC Facilitates Amyloid Formation

“…The negatively charged lysolipids (lipids with one hydrophobic tail that form micelle) LPG accelerate fibrillation of FapC around its cmc (critical micelle concentration) via strong interactions with FapC and stabilising intermediates whereas zwitterionic lysolipids LPC only show a weak interaction with FapC [40]. Previously we have shown that positively charged Lys residues have a strong effect in the interaction of Phenol Soluble Modulin (PSM) from S.aureus with negatively charged proteins/molecules like fibrinogen and heparin [11,12]. Similarly, we believe that the 14 Lys residues present in FapC (there are no Arg residues) can promote electrostatic interactions between FapC and negatively charged vesicles.…”

“…Amyloid formation is often highly sensitive to environmental conditions. Biomolecules such as biosurfactants [10], lipopolysaccharides (LPS) [10], heparin [11], fibrinogen [12] and chaperones [13] can induce or inhibit fibrillation. During transport over the periplasmic space and after export from the outer membrane, FapC has multiple opportunities to interact with membrane surfaces.…”