Prion and Nonprion Amyloids

Abstract

Yeast prion determinants are related to polymerization of some proteins into amyloid-like fibers. The [PSI+] determinant reflects polymerization of the Sup35 protein. Fragmentation of prion polymers by the Hsp104 chaperone represents a key step of the prion replication cycle. The frequency of fragmentation varies depending on the structure of the prion polymers and defines variation in the prion phenotypes, e.g., the suppressor strength of [PSI+] and stability of its inheritance. Besides [PSI+], overproduction of Sup35 can produce nonheritable phenotypically silent Sup35 amyloid-like polymers. These polymers are fragmented poorly and are present due to efficient seeding with the Rnq1 prion polymers, which occurs by several orders of magnitude more frequently than seeding of [PSI+] appearance. Such Sup35 polymers resemble human nonprion amyloids by their nonheritability, mode of appearance and increased size. Thus, a single protein, Sup35, can model both prion and nonprion amyloids. In yeast, these phenomena are distinguished by the frequency of polymer fragmentation. We argue that in mammals the fragmentation frequency also represents a key factor defining differing properties of prion and nonprion amyloids, including infectivity. By analogy with the Rnq1 seeding of nonheritable Sup35 polymers, the “species barrier” in prion transmission may be due to seeding by heterologous prion of nontransmissible type of amyloid, rather than due to the lack of seeding.

Acknowledgements

The work in the authors' laboratory was supported by the Wellcome Trust, Howard Hughes Medical Institute, International Science and Technology Center and Russian Foundation for Basic Research.

Note

This manuscript has been previously published: Kushnirov VV, Vishnevskaya AB, Alexandrov IM, Ter-Avanesyan MD. Chernoff Y. Prion and Nonprion Amyloids: A Comparison Inspired by the Yeast Sup35 Protein. Protein-Based Inheritence Austin and New York Landes Bioscience and Kluwer Academic Press 2007; 73 - 79

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Figures and Tables

Figure 1 Structure of Sup35 polymers. Amyloid-like fiber is formed by the Sup35N domains. N, M and C, domains of Sup35.

Figure 2 Prion polymers and aggregates. The aggregates represent irregular complexes containing multiple prion polymers and some additional proteins. In case of Sup35 these are presumably Sup35 functional partners, polyribosomes and chaperones.

Figure 3 Replication of yeast Sup35 prion polymers. Polymers grow by joining Sup35 monomers and multiply by fragmentation with the Hsp104 chaperone.