Strain phenomenon in protein aggregation

S of yeast and mammalian prions introduced the idea that the protein aggregates can exist in multiple stable conformations that can be propagated by seeding. These conformational states (aka strains) were shown to have distinct physical (secondary structure, stability) and biological (cytotoxicity, infectivity) properties. For mammalian prions they were also tied to differences in disease pathology and incubation time. It was later shown that this phenomenon is not limited to prion proteins, and distinct conformational states of amyloid fibrils and oligomers derived from a variety of proteins can be propagated both in vitro and in vivo. Moreover, in some cases these conformations were preserved even when propagated into a protein with a different sequence. There is now an increasing body of evidence that strain phenomenon is a generic feature of protein aggregation, and characteristic features of amyloid strains can be transmitted between unrelated sequences. For decades our understanding of protein structure has been driven by Anfinsen’s dogma: a protein possesses a single native structure that is determined only by its amino acid sequence. Discovery that proteins can be infectious, and that this infectivity is due to an autocatalytic conversion of a protein into a different, misfolded conformation, represented a significant milestone in biology. Together with the concept of intrinsic disorder this discovery showed that protein conformation can be plastic and malleable. Initially autocatalytic conversion of proteins into misfolded, β-sheet rich conformation was proposed in order to explain the unusual properties of transmissible spongiform encephalophathies (TSEs) where prion protein (PrP) serves as an infectious agent. These diseases are caused by misfolding and aggregation of prion protein (PrP) into fibrillar aggregates (PrP). PrP fibrils can be transmitted between individuals and propagate themselves by seeding. Seeding process involves binding of a PrP monomer to a PrP fibril followed by conversion of this monomer to a conformation closely resembling that of an initial aggregate. This mechanism of propagation is common for all amyloids. However, not all of them are infectious in vivo. Other factors such as the ability of protein aggregates to fragment and self-propagate in physiological conditions and their resistance to clearance are necessary to make the amyloid infectious. An important feature of TSEs is the presence of multiple disease strains. Strains have been initially defined as the isolates of infectious prions characterized by the specific incubation time of the disease, characteristic neuropathological lesions, and in some cases certain patterns in animal behavior that are faithfully recapitulated upon serial passage. For example, Hyper and Drowsy TSE strains lead to, respectively, increased and decreased activity of infected animals. It has been shown that different disease strains correspond to distinct conformations of PrP fibrils as they can be differentiated by the protease cleavage pattern, antibody Strain phenomenon in protein aggregation