Maintaining proteome health is important for cell survival. Nucleic acids possess the ability to prevent protein aggregation more efficiently than traditional chaperone proteins. In this study, we explore the sequence specificity of the chaperone activity of nucleic acids. Evaluating over 500 nucleic acid sequences' effects on protein aggregation, we show that the holdase chaperone effect of nucleic acids is sequence-dependent. G-Quadruplexes prevent protein aggregation via quadruplex:protein oligomerization. They also increase the folded protein level of a biosensor in E. coli. These observations contextualize recent reports of quadruplexes playing important roles in aggregation-related diseases, such as fragile X and amyotrophic lateral sclerosis (ALS), and provide evidence that nucleic acids have the ability to modulate the folding environment of E. coli.
Maintaining proteome health is important for cell survival. Nucleic acids possess the ability to prevent aggregation up to 300-fold more efficiently than traditional chaperone proteins. In this study, we explore the sequence specificity of the chaperone activity of nucleic acids. Evaluating over 500 nucleic acid sequences' effects on aggregation, we demonstrate that the holdase chaperone effect of nucleic acids is highly sequence dependent. Quadruplexes are found to have especially potent effects on aggregation with many different proteins via quadruplex:protein oligomerization. These observations contextualize recent reports of quadruplexes playing important roles in aggregation-related diseases, such as Fragile X and Amyotrophic lateral sclerosis (ALS). Main Text:Chaperones are a diverse group of proteins and other molecules that regulate proteostasis (1) in the cell by preventing protein aggregation (holdases) and helping protein folding (foldases). Recently, molecules other than traditional protein chaperones have been shown to play important roles in these processes (2, 3). We recently showed that nucleic acids can possess potent holdase activity, with the best sequences having higher holdase activity than any previously characterized chaperone (4). Nucleic acids can also collaborate with Hsp70 to help protein folding, acting similarly to small heat shock proteins (4-7). Nucleic acids can also bring misfolded proteins to stress granules (8), and are a primary component of the nucleolus, which was recently shown to store misfolded proteins under stress conditions (9). However, the structural characteristics, sequence dependence, and mechanistic understanding of how nucleic acids act as chaperones remains unclear.A critical question in understanding the holdase activity of nucleic acids is whether this activity is sequence specific? Previously, we showed that polyA, polyT, polyG, and polyC prevented aggregation with varying kinetics, suggesting that sequence specificity was possible (4). Here, we test sequence specificity by examining over 500 nucleic acids of varying sequence for
Previous studies have shown that nucleic acids can nucleate protein aggregation in disease-related proteins, but in other cases, they can act as molecular chaperones that prevent protein aggregation, even under extreme conditions. In this study, we describe the link between these two behaviors through a combination of electron microscopy and aggregation kinetics. We find that two different proteins become soluble under harsh conditions through oligomerization with DNA. These DNA/protein oligomers form ''networks,'' which increase the speed of oligomerization. The cases of DNA both increasing and preventing protein aggregation are observed to stem from this enhanced oligomerization. This observation raises interesting questions about the role of nucleic acids in aggregate formation in disease states.
How nucleic acids interact with proteins, and how they affect protein folding, aggregation, and misfolding is a still‐evolving area of research. Considerable effort is now focusing on a particular structure of RNA and DNA, G‐quadruplexes, and their role in protein homeostasis and disease. In this state‐of‐the‐art review, we track recent reports on how G‐quadruplexes influence protein aggregation, proteolysis, phase separation, and protein misfolding diseases, and pose currently unanswered questions in the advance of this scientific field.
Maintaining the health of the proteome is a critical cellular task. Recently, we found G-quadruplex (G4) nucleic acids are especially potent at preventing protein aggregation in vitro and could at least indirectly improve the protein folding environment of Escherichia coli . However, the roles of G4s in protein folding were not yet explored. Here, through in vitro protein folding experiments, we discover that G4s can accelerate protein folding by rescuing kinetically trapped intermediates to both native and near-native folded states. Time-course folding experiments in E. coli further demonstrate that these G4s primarily improve protein folding quality in E. coli as opposed to preventing protein aggregation. The ability of a short nucleic acid to rescue protein folding opens up the possibility of nucleic acids and ATP-independent chaperones to play considerable roles in dictating the ultimate folding fate of proteins.
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