Prions of fungi: inherited structures and biological roles

Abstract

The term 'prion' means an infectious protein that does not need an accompanying nucleic acid. There are six fungal prions, including four self-propagating amyloids and two enzymes that are necessary to activate their inactive precursors. Here we explore the scope of the prion phenomenon, the biological and evolutionary roles of prions, the structural basis of the amyloid prions and the prominent role of chaperones (proteins that affect the folding of other proteins) and other cellular components in prion generation and propagation.

Figure 1. Yeast and fungal amyloid prions

The soluble forms of Ure2p and Sup35p function in nitrogen regulation and transcription termination, respectively. Their amyloid forms are non-functional. Soluble Rnq1p has no known cellular function and the amyloid form can sporadically prime polymerization of Sup35p or Ure2p resulting in generation of the [PSI⁺] and [URE3] prions. The soluble form of the HETs protein has no known function, but its amyloid form is necessary for heterokaryon incompatibility, a limitation on fusion of neighboring colonies. Red domains are apparently unstructured in the native form and become amyloid in the prion form. Green shapes are natively structured domains.

Figure 2. Sup35NM structure model

Parallel in-register β-sheet structure of the prion domain of Sup35p. β-strands (blue arrows) run perpendicular to the long axis of the filaments and are connected by loops (green). A given residue (such as Tyr101) is aligned with the same residue in the adjacent strand (red). This structure can explain the transmission of prion variant information, as the entirety of each prion domain contacts those of the next and previous molecules in the filament.

Figure 3. Chaperones and prions

Chaperones (tan shapes) may help prion propagation by breaking long amyloid filaments into shorter ones thereby creating new growth points for amyloid formation (seeds). Chaperones may also hinder prion propagation by binding to the ends of filaments thereby blocking their growth or by binding to the soluble form of the protein thereby preventing the protein from joining the chain. Certainly Hsp104, and probably the cytoplasmic Ssa Hsp70s, have a role in filament breakage.

Figure 4. Prion variants & species barrier

Sheep scrapie shows limited infectivity for goats, a phenomenon called the species barrier. The overlap of conformations that donor and recipient proteins can assume determine the strength of the species barrier. As species B and C have prion proteins able to assume many similar amyloid conformations, there will be little species barrier between them. Prion protein of species A and C have few common conformations and so will have a high species barrier. A prion variant (such as bovine spongiform encephalopathy) due to an amyloid conformation that can be assumed by the protein sequence of many species will have a broad host range.