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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. [ABSTRACT FROM AUTHOR]

Liquid-liquid phase condensation governs a wide range of protein-protein and protein-RNA interactions in vivo and drives the formation of membrane-less compartments such as the nucleolus and stress granules. We have a broad overview of the importance of multivalency and protein disorder in driving liquid-liquid phase transitions. However, the large and complex nature of key proteins and RNA components involved in forming condensates such as stress granules has inhibited a detailed understanding of how condensates form and the structural interactions that take place within them. In this work, we focused on the small human SERF2 protein. We show here that SERF2 contributes to the formation of stress granules. We also show that SERF2 specifically interacts with non-canonical tetrahelical RNA structures called G-quadruplexes, structures which have previously been linked to stress granule formation. The excellent biophysical amenability of both SERF2 and RNA G4 quadruplexes has allowed us to obtain a high-resolution visualization of the multivalent protein-RNA interactions involved in liquid-liquid phase transitions. Our visualization has enabled us to characterize the role that protein disorder plays in these transitions, identify the specific contacts involved, and describe how these interactions impact the structural dynamics of the components involved in liquid-liquid phase transitions, thus enabling a detailed understanding of the structural transitions involved in early stages of ribonucleoprotein condensate formation.

The SERF family of proteins were originally discovered for their ability to accelerate amyloid formation. Znf706 is an uncharacterized protein whose N-terminus is homologous to SERF proteins. We show here that human Znf706 can promote protein aggregation and amyloid formation. Unexpectedly, Znf706 specifically interacts with stable, non-canonical nucleic acid structures known as G-quadruplexes. G-quadruplexes can affect gene regulation and suppress protein aggregation; however, it is unknown if and how these two activities are linked. We find Znf706 binds preferentially to parallel G-quadruplexes with low micromolar affinity, primarily using its N-terminus, and upon interaction, its dynamics are constrained. G-quadruplex binding suppresses Znf706's ability to promote protein aggregation. Znf706 in conjunction with G-quadruplexes therefore may play a role in regulating protein folding. RNAseq analysis shows that Znf706 depletion specifically impacts the mRNA abundance of genes that are predicted to contain high G-quadruplex density. Our studies give insight into how proteins and G-quadruplexes interact, and how these interactions affect both partners and lead to the modulation of protein aggregation and cellular mRNA levels. These observations suggest that the SERF family of proteins, in conjunction with G-quadruplexes, may have a broader role in regulating protein folding and gene expression than previously appreciated.