Emergence and evolution of yeast prion and prion-like proteins

Abstract

Background: Prions are transmissible, propagating alternative states of proteins, and are usually made from the fibrillar, beta-sheet-rich assemblies termed amyloid. Prions in the budding yeast Saccharomyces cerevisiae propagate heritable phenotypes, uncover hidden genetic variation, function in large-scale gene regulation, and can act like diseases. Almost all these amyloid prions have asparagine/glutamine-rich (N/Q-rich) domains. Other proteins, that we term here 'prionogenic amyloid formers' (PAFs), have been shown to form amyloid in vivo, and to have N/Q-rich domains that can propagate heritable states in yeast cells. Also, there are >200 other S.cerevisiae proteins with prion-like N/Q-rich sequence composition. Furthermore, human proteins with such N/Q-rich composition have been linked to the pathomechanisms of neurodegenerative amyloid diseases.

Results: Here, we exploit the increasing abundance of complete fungal genomes to examine the ancestry of prions/PAFs and other N/Q-rich proteins across the fungal kingdom. We find distinct evolutionary behavior for Q-rich and N-rich prions/PAFs; those of ancient ancestry (outside the budding yeasts, Saccharomycetes) are Q-rich, whereas N-rich cases arose early in Saccharomycetes evolution. This emergence of N-rich prion/PAFs is linked to a large-scale emergence of N-rich proteins during Saccharomycetes evolution, with Saccharomycetes showing a distinctive trend for population sizes of prion-like proteins that sets them apart from all the other fungi. Conversely, some clades, e.g. Eurotiales, have much fewer N/Q-rich proteins, and in some cases likely lose them en masse, perhaps due to greater amyloid intolerance, although they contain relatively more non-N/Q-rich predicted prions. We find that recent mutational tendencies arising during Saccharomycetes evolution (i.e., increased numbers of N residues and a tendency to form more poly-N tracts), contributed to the expansion/development of the prion phenomenon. Variation in these mutational tendencies in Saccharomycetes is correlated with the population sizes of prion-like proteins, thus implying that selection pressures on N/Q-rich protein sequences against amyloidogenesis are not generally maintained in budding yeasts.

Conclusions: These results help to delineate further the limits and origins of N/Q-rich prions, and provide insight as a case study of the evolution of compositionally-defined protein domains.

Fig. 1

The taxonomic levels considered for orthologs of prions and PAFs. The number of species is given for each level

Fig. 2

Summary of trends observed for the evolution of prions and other PAFs. The evolution of each prion/PAF is summarized. They are listed far right with prion gene names in bold, other PAFs in italics. Q-rich prions/PAFs are labeled with a green dot, N-rich with a red dot. Moving from right to left, we move deeper into the evolutionary past to a more ancient last common ancestor, and wider to more divergent clades of the fungi kingdom. First, we consider conservation in other Saccharomycetes, then in other Ascomycota beyond the Saccharomycetes, then finally in other Fungi beyond the Ascomycota. The fraction of orthologs with N/Q-rich domains in each of these groupings that are designated N-rich is listed. Where this is >0.5 the dot is red, otherwise it is green. At the bottom of these three columns is listed the overall fraction of N-rich

Fig. 3

Overall trend in occurrence of prion-like proteins. a Summary of the trend presented in detail in Additional file 3: Figure S1 for the numbers of N/Q-rich proteins. The heatmap colour coding is the same as in that figure. The leaf nodes of this schematic tree as for the Ascomycota and Basidiomycota ‘trend clades’ from Additional file 3: Figure S1, i.e. the clades into which the tree can be split according to the obvious trends within these clades. The overall percentages are listed after the clade names. b Same plot as (A), except it is for the union of all of the prion predictions by the PLAAC and PAPA programs. Heatmap colour coding according to the numbers in column 2 of Additional file 7: Figure S3 is used. c Same plot as (A), except it is summarizing the trend presented in detail in Additional file 7: Figure S3 for total numbers of non-N/Q-rich prion predictions. To define non-N/Q-rich prion predictions, we used a strict threshold for N/Q bias (P = 1×10⁻⁵). The heatmap colour coding is the same as for Additional file 7: Figure S3

Fig. 4

Numbers of intrinsically disordered proteins (IDPs) versus numbers of N/Q-rich proteins or prion predictions. a Plot of number of IDPs versus numbers of N/Q-rich proteins. Proteins with ID regions >30 residues were counted as IDPs. We only consider IDPs that do not have N/Q-rich domains in the IDP totals. Saccharomycetes species are red points, and non-Saccharomycetes blue. The trend line for both is shown. The Pearson correlation coefficients are: R = 0.135 (P = 0.03) Saccharomycetes, R = 0.358 (P < 1e–07) non-Saccharomycetes. b Same as (A), but with IDPs versus predicted prion proteins (the union of PAPA and PLAAC predictions for each proteome) that are N/Q-rich. R = 0.139 (P = 0.03) Saccharomycetes, R = 0.444 (P < 1e–07) non-Saccharomycetes. The IDP totals are for those that have no prion predictions in them (by either PAPA or PLAAC), i.e. all of the proteins with prion predictions are removed. c Same as (A), but for the subset of predicted prions that are not N/Q-rich. R = 0.49 (P < 1e–07) Saccharomycetes, R = 0.422 (P < 1e–07) non-Saccharomycetes. To define non-N/Q-rich prion predictions, we use a strict threshold for N/Q bias (P = 1×10⁻⁵). As above in part (B), the IDP totals are for those that have no prion predictions in them