Abstract
The infective ability of the opportunistic pathogen Staphylococcus aureus, recognized as the most frequent cause of biofilm-associated infections, is associated with biofilm-mediated resistance to host immune response. Phenol-soluble modulins (PSM) comprise the structural scaffold of S. aureus biofilms through self-assembly into functional amyloids, but the role of individual PSMs during biofilm formation remains poorly understood and the molecular pathways of PSM self-assembly are yet to be identified. Here we demonstrate high degree of cooperation between individual PSMs during functional amyloid formation. PSMα3 initiates the aggregation, forming unstable aggregates capable of seeding other PSMs resulting in stable amyloid structures. Using chemical kinetics we dissect the molecular mechanism of aggregation of individual PSMs showing that PSMα1, PSMα3 and PSMβ1 display secondary nucleation whereas PSMβ2 aggregates through primary nucleation and elongation. Our findings suggest that various PSMs have evolved to ensure fast and efficient biofilm formation through cooperation between individual peptides.
Highlights
Aggregated proteins in the form of functional amyloids are widespread in nature (Pham et al, 2014)
Previous studies have shown that Phenol-soluble modulins (PSM) from S. aureus form functional amyloids that contribute to biofilm integrity and provide resistance to disruption, which is critical to the virulence of medical device-associated infections (Marinelli et al, 2016; Schwartz et al, 2012)
We have conducted a combination of detailed kinetic analysis with structural and morphological analysis to gain insights into the molecular and mechanistic steps, to determine how functional amyloid of PSMs, the biofilm determinant of S. aureus, forms and grows
Summary
Aggregated proteins in the form of functional amyloids are widespread in nature (Pham et al, 2014). The well-studied curli machinery in Escherichia coli (Evans and Chapman, 2014), Fap system in Pseudomonas fluorescens (Dueholm et al, 2010), TasA system in Bacillus subtilis (Romero et al, 2010), along with phenol-soluble modulins (PSMs) in Staphylococcus aureus (Schwartz et al, 2012) are some of the major bacterial functional amyloid systems that have been reported so far. For S. aureus biofilm formation PSMs have been recognized as a crucial factor In their soluble monomeric form they hinder host immune response by recruiting, activating, and lysing human neutrophils while promoting biofilm dissociation (Schwartz et al, 2012). Despite the formation of functional amyloids in S. aureus by PSMs, many questions remain about the intrinsic molecular mechanism by which they self-assemble and what molecular events trigger the formation of fibrillar structure from their monomeric precursor peptide. We apply a combination of chemical kinetic studies along with biophysical techniques to explore the relative importance of different microscopic steps involved in the mechanism of fibril formation of PSMs peptides
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