Prion-like domains as epigenetic regulators, scaffolds for subcellular organization, and drivers of neurodegenerative disease

Abstract

Key challenges faced by all cells include how to spatiotemporally organize complex biochemistry and how to respond to environmental fluctuations. The budding yeast Saccharomyces cerevisiae harnesses alternative protein folding mediated by yeast prion domains (PrDs) for rapid evolution of new traits in response to environmental stress. Increasingly, it is appreciated that low complexity domains similar in amino acid composition to yeast PrDs (prion-like domains; PrLDs) found in metazoa have a prominent role in subcellular cytoplasmic organization, especially in relation to RNA homeostasis. In this review, we highlight recent advances in our understanding of the role of prions in enabling rapid adaptation to environmental stress in yeast. We also present the complete list of human proteins with PrLDs and discuss the prevalence of the PrLD in nucleic-acid binding proteins that are often connected to neurodegenerative disease, including: ataxin 1, ataxin 2, FUS, TDP-43, TAF15, EWSR1, hnRNPA1, and hnRNPA2. Recent paradigm-shifting advances establish that PrLDs undergo phase transitions to liquid states, which contribute to the structure and biophysics of diverse membraneless organelles. This structural functionality of PrLDs, however, simultaneously increases their propensity for deleterious protein-misfolding events that drive neurodegenerative disease. We suggest that even these PrLD-misfolding events are not irreversible and can be mitigated by natural or engineered protein disaggregases, which could have important therapeutic applications.

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

“…2). The entire C-terminal region of ∼160 amino acids is considered low complexity in that it is highly enriched in only four amino acids (glycine, glutamine, serine, and asparagine), which are similar to the residues enriched in yeast prion domains (March et al 2016). Some mutations are predicted to increase propensity for phosphorylation (Kabashi et al 2008) and spontaneous aggregation (Johnson et al 2009), while others are proposed to influence amyloid-like states that are available to TDP-43 via a short stretch of mostly Q/N (Fuentealba et al 2010;Budini et al 2012;Mompean et al 2016).…”

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

“…However, it is unclear how the cell limits the aggregation propensity of these domains and if therapies targeting these domains could be developed. Efforts to enhance the ability of cells to disassemble inclusions using disaggregase chaperones show promise (Jackrel & Shorter, 2015; March et al , 2016). We thought post‐translational modifications would be an alternative and potentially more pharmacologically tractable strategy to disrupt assembly directly at its source.…”

Ubiquilin 2: Shuttling Clients Out of Phase?

“…Once stress ebbs, SGs resolve to liberate their proteins and RNAs, which may resume their functions or be degraded. SGs assemble via liquid-liquid phase separation (LLPS) driven by multivalent RNA-RNA, RNA-protein, and protein-protein interactions, including multiple transient contacts between low-complexity, prion-like domains (PrLDs) (March et al, 2016; Protter and Parker, 2016). Excessive SG assembly or defective SG dissolution after stress is linked with neurodegeneration and may reflect altered phase behavior of SG-resident RNA-binding proteins (RBPs) or altered protein-degradation programs (March et al, 2016).…”

“…SGs assemble via liquid-liquid phase separation (LLPS) driven by multivalent RNA-RNA, RNA-protein, and protein-protein interactions, including multiple transient contacts between low-complexity, prion-like domains (PrLDs) (March et al, 2016; Protter and Parker, 2016). Excessive SG assembly or defective SG dissolution after stress is linked with neurodegeneration and may reflect altered phase behavior of SG-resident RNA-binding proteins (RBPs) or altered protein-degradation programs (March et al, 2016). Ubiquilins (UBQLNs) are a family of four (−1, −2, −3, and −4) paralogous molecular chaperones that shuttle ubiquitylated clients to the proteasome for degradation (Hjerpe et al, 2016; Itakura et al, 2016).…”

“…UBQLN2 also contains a proline-rich region (Pxx) (residues 491–538), which is not found in other UBQLNs. Like UBQLN1, UBQLN2 harbors a PrLD (residues 339–462), which overlaps with STI1-II (Figure 1A) (March et al, 2016). PrLDs are low-complexity domains with a distinctive amino acid composition enriched in glycine and uncharged polar residues such as glutamine, asparagine, tyrosine, and serine, which resemble prion domains that enable various yeast proteins to form prions (March et al, 2016).…”