Fold modulating function: bacterial toxins to functional amyloids

Abstract

Many bacteria produce cytolytic toxins that target host cells or other competing microbes. It is well known that environmental factors control toxin expression, however, recent work suggests that some bacteria manipulate the fold of these protein toxins to control their function. The β-sheet rich amyloid fold is a highly stable ordered aggregate that many toxins form in response to specific environmental conditions. When in the amyloid state, toxins become inert, losing the cytolytic activity they display in the soluble form. Emerging evidence suggest that some amyloids function as toxin storage systems until they are again needed, while other bacteria utilize amyloids as a structural matrix component of biofilms. This amyloid matrix component facilitates resistance to biofilm disruptive challenges. The bacterial amyloids discussed in this review reveal an elegant system where changes in protein fold and solubility dictate the function of proteins in response to the environment.

Keywords: aggregation; bacterial toxin; bifunctional protein; biofilm; functional amyloid.

FIGURE 1

Curli biogenesis model. The curli system in Escherichia coli is a highly controlled process that only expressed the curli amyloid under conditions that promote biofilm formation. The system is transcriptionally controlled by the master regulator CsgD which increases the transcription of the major and minor subunits CsgA and CsgB. All Csg proteins other than CsgD are secreted through the Sec secretion pathway into the periplasm where CsgA, CsgB, and CsgF are then transclocated outside of the cell through the CsgG pore complex. CsgE and CsgF aid in proper export and localization of the structural components while CsgC has a less well understood role in the periplasm.

FIGURE 2

Phenol soluble modulins as bifunctional proteins. (A) Staphylococcus aureus produces Phenol soluble modulins (PSM) proteins that have been found to have many diverse functions. As soluble molecules, they are able to stimulate chemotaxis of neutrophils as well as aid S. aureus escape from the phagolysosome upon phagocytosis. Additionally, soluble PSMs can disperse biofilms as well as be proteolytically processed into PSM derivatives of phenol-soluble modulins (dPSMs) that can kill niche competing bacteria. Once polymerized into amyloid fibers, PSMs provide functional support to the biofilm community that prevents degradation by biofilm dispersing enzymes. The interactions between PSM fibers and immune cells have yet to be characterized. (B) Transmission electron microscopy of a S. aureus biofilm that is producing PSM amyloids fibers. (C) S. aureus biofilm cells under conditions where amyloid fibers are not detected.