The emergence of bacterial prions

Prions are proteins that can adopt at least 2 distinct conformations (structural states), being one of them soluble, either natively folded or intrinsically disordered, and the other an aggregated fibrillar structure, termed amyloid, made of stacked ß-strands contributed by the individual protein molecules [1].Amyloids propagate their conformation to soluble protein molecules of their same kind by contact, capturing them as new building blocks of their elongating fibers.Conformational variants (i.e., alternative 3D folds for the same protein sequence) of an amyloid assembly can be propagated as distinct prion strains vertically with cell division, from mother to daughter cells, for many generations constituting a case for cytoplasmatic, non-mendelian epigenetic inheritance [1].After the pioneering discovery of the mammalian prion protein PrP [2], the whole field was boosted by findings in the yeast Saccharomyces cerevisiae, in which several transcriptional and translational factors (such as Sup35 and Ure2) were shown to aggregate as amyloids, resulting in loss-of-function phenotypes ([PSI + ] and [URE3], respectively) [3,4].Alternative strains of yeast prions were horizontally transmissible between cells while mating through cytoduction (i.e., cytoplasmatic mixing) [5].In yeast, depending on the protein, its amyloid state either elicits a functionally adaptive phenotypic change or becomes cytotoxic and deleterious [6,7].Horizontal transmission as an infectious agent has been recently described also for amyloid proteins involved in human neurodegenerative diseases such αsynuclein, Tau, the ß-amyloid peptides, and TDP-43, self-propagating as prion-like proteins (or prionoids) between cells within different areas of the central nervous system [8].In bacteria, as exemplified by the Escherichia coli biofilm scaffolding protein CsgA, some extracellular secreted proteins rely on a complex, dedicated protein machinery for their regulated assembly as functional amyloids, with defined fibrillar structures and physiological roles [9].These are distinct to prions, in which the soluble monomers are functional while the amyloid fibrils that they assemble, usually polymorphic, lose that function [8].Mining in prokaryotic proteomes identified many proteins with potential prion forming domains (PrDs), typically intrinsically disordered (IDPs) and with overall polar residue composition, similar to those in yeast prions [10,11].However, so far detailed experimental characterization of bacterial prions is restricted to individual domains in just 3 proteins adopting an amyloid state (Fig 1). Pseudomonas plasmid replication protein RepAThe N-terminal domain (WH1) in the replication protein RepA of the Pseudomonas savastanoi plasmid pPS10 assembles amyloid filaments in vitro upon binding to a specific DNA sequence [12].In the full-length RepA, when bound to DNA repeats located at the origin of replication (oriV), WH1 builds a functional amyloid: an oligomeric superhelical nucleoprotein complex that bridges together 2 copies of the plasmid to hinder their untimely replication [13,14] (Fig 1A).In such oligomers, the WH1 domain is engaged with itself through β-sheet