RNA-binding proteins with prion-like domains in health and disease

Abstract

Approximately 70 human RNA-binding proteins (RBPs) contain a prion-like domain (PrLD). PrLDs are low-complexity domains that possess a similar amino acid composition to prion domains in yeast, which enable several proteins, including Sup35 and Rnq1, to form infectious conformers, termed prions. In humans, PrLDs contribute to RBP function and enable RBPs to undergo liquid–liquid phase transitions that underlie the biogenesis of various membraneless organelles. However, this activity appears to render RBPs prone to misfolding and aggregation connected to neurodegenerative disease. Indeed, numerous RBPs with PrLDs, including TDP-43 (transactivation response element DNA-binding protein 43), FUS (fused in sarcoma), TAF15 (TATA-binding protein-associated factor 15), EWSR1 (Ewing sarcoma breakpoint region 1), and heterogeneous nuclear ribo-nucleoproteins A1 and A2 (hnRNPA1 and hnRNPA2), have now been connected via pathology and genetics to the etiology of several neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy. Here, we review the physiological and pathological roles of the most prominent RBPs with PrLDs. We also highlight the potential of protein disaggregases, including Hsp104, as a therapeutic strategy to combat the aberrant phase transitions of RBPs with PrLDs that likely underpin neurodegeneration.

A Genetic Tool to Track Protein Aggregates and Control Prion Inheritance

“…We confirmed that this loss of yTRAP signal for Hrp1 and another top candidate, Ngr1, was accompanied by microscopic foci formation (Figure 6B). Hrp1 is the closest yeast homolog of human hnRNPA1, the aggregation of which is associated with both MSP and ALS (Harrison and Shorter, 2017). Thus, we decided to focus on Hrp1 for further analysis.…”

“…These genes are heavily enriched for RNA-binding and RNA-processing activity, including many aggregation-prone proteins associated with fatal neurodegenerative diseases (Harrison and Shorter, 2017). However, natural assemblies/aggregates of RNA-binding proteins (RBPs) are important for RNA storage, processing, and degradation (Protter and Parker, 2016).…”

Environment-transformable sequence–structure relationship: a general mechanism for proteotoxicity

“…It has been well established that, at a molecular level, long-term memory is characterized by its requirement for changing the profiles of gene expression which is mainly implemented by the RNA-binding proteins with the prion-like domains (Shorter and Lindquist 2005;Rayman and Kandel 2017;Sudhakaran and Ramaswami 2017). However, even in the human genome, it is likely that there exist <240 RNA-binding proteins with the prion-like domains (Harrison and Shorter 2017). So how can such a limited number of the RNA-binding proteins produce a giant amount of the gene expression profiles to consolidate long-term memory and/or even more generally cellular memory?…”

“…1f), which are enriched in polar and uncharged amino acids such as Gln, Asn, Ser, Gly and Tyr. As they share compositional similarity to the yeast prions such as Sup35, they are thus called Bprion-like^domains (Shorter and Lindquist 2005;Michelitsch and Weissman 2000;Chien and Weissman 2001;Han et al 2012;Harrison and Shorter 2017). Recently,~240 out of~20,000 human protein-coding genes (~1.2%) were shown to contain at least one prion-like domain, and, interestingly, human proteins containing the prion-like domains are over-represented by those critically interacting with RNA/DNA including TDP-43 and FUS proteins.…”

“…Furthermore,~30% proteins of both high-and low-complexity sequences can fold in the membrane environments (b) disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and multisystem proteinopathy (MSP). Most unexpectedly, almost all disease-causing mutations are located within their low-complexity domains (Han et al 2012;Harrison and Shorter 2017;Ling et al 2013;Lim et al 2016a;Conicella et al 2016).…”