Yeast prions and human prion-like proteins: sequence features and prediction methods

Abstract

Prions are self-propagating infectious protein isoforms. A growing number of prions have been identified in yeast, each resulting from the conversion of soluble proteins into an insoluble amyloid form. These yeast prions have served as a powerful model system for studying the causes and consequences of prion aggregation. Remarkably, a number of human proteins containing prion-like domains, defined as domains with compositional similarity to yeast prion domains, have recently been linked to various human degenerative diseases, including amyotrophic lateral sclerosis (ALS). This suggests that the lessons learned from yeast prions may help in understanding these human diseases. In this review, we examine what has been learned about the amino acid sequence basis for prion aggregation in yeast, and how this information has been used to develop methods to predict aggregation propensity. We then discuss how this information is being applied to understand human disease, and the challenges involved in applying yeast prediction methods to higher organisms.

Generating new prions by targeted mutation or segment duplication

“…In particular, full-length Yck1 has been shown to stimulate [PSI + ] formation when overexpressed (42), suggesting that the fulllength protein may have some prion-like activity. Finally, regions outside of the Sup35 PFD can influence prion activity (12), so although we showed that a small number of mutations can confer prion activity on the Puf4 and YLR177W PrLDs, these domains may still not act as prions in their native context. Additionally, factors such as expression level, cellular localization, and binding partners likely all affect prion activity in ways that have not yet been fully defined.…”

Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity

“…We next sought to test the hypothesis that phosphorylation could disrupt FUS self‐association and aggregation by altering the biophysical properties of the LC. One measure of the self‐assembly/aggregation propensity of disordered domains is a quantitative assessment of their “prion‐like” character, a name given to sequences enriched in polar residues and lacking charged and aliphatic residues as found in yeast prion proteins (Cascarina & Ross, 2014). Mimicking phosphorylation at S/TQ positions by substitution of serine or threonine with the negatively charged residue glutamic acid (glutamate) results in a marked decrease in the prion‐like propensity as measured by the PLAAC algorithm (Fig 1A; Lancaster et al , 2014), which identifies probable prion‐like protein segments.…”

[PSI+] turns 50

“…49,50 These properties have been used to help identify several other prions in S. cerevisiae although it is very likely that many others exist. 48,51 It is worth pointing out that, in addition to the effect of Reed Wickner's 1994 paper on the direction of [PSI C ] prion studies, it "changed the water on the beans" for prion biology in a more general way. As we note above, we think it is fair to say that acceptance of Stanley Prusiner's prion hypothesis had until then been grudging, in spite of papers from his laboratory and others illuminating the molecular basis of spongiform encephalopathies.…”