Interplay between disordered regions in RNAs and proteins modulates interactions within stress granules and processing bodies

Abstract

Condensation, or liquid-like phase separation, is a phenomenon indispensable for the spatiotemporal regulation of molecules within the cell. Recent studies indicate that the composition and molecular organization of phase-separated organelles such as Stress Granules (SGs) and Processing Bodies (PBs) are highly variable and dynamic. A dense contact network involving both RNAs and proteins controls the formation of SGs and PBs and an intricate molecular architecture, at present poorly understood, guarantees that these assemblies sense and adapt to different stresses and environmental changes. Here, we investigated the physico-chemical properties of SGs and PBs components and studied the architecture of their interaction networks. We observed that proteins and RNAs establishing the largest amount of contacts have distinct structural characteristics. More specifically, we found that structural disorder is enriched in all protein-RNA, protein-protein and RNA-RNA interactions. Intriguingly, enrichment in the disorder of proteins is linked to increased number of interactions with single-stranded regions in RNAs. Our findings support the hypothesis that SGs and PBs can quickly assemble and disassemble thanks to the activity of unfolded domains in proteins and single-stranded regions in RNAs, guaranteeing the formation of dynamic contacts.

Mechanisms tailoring the expression of heat shock proteins to proteostasis challenges

“…Translation repression is accompanied by changes in the physical properties of the cytoplasmic milieu. Stress triggers RNAs and proteins to phase separate and form SGs and PBs that contain untranslated, long, and highly unstructured mRNAs and proteins that participate in translation, transcription, splicing, and decay (72,(120)(121)(122). SGs and PBs are dynamic membrane structures assembled by Liquid-Liquid phase transition that favor stress tolerance and promote cellular fitness (123)(124)(125)(126)(127).…”

A high-throughput approach to predict A-to-I effects on RNA structure indicates a change of double-stranded content in non-coding RNAs

“…As a result, one molecule of RNA can bind several proteins (3, 4). This property is crucial for the formation of ribonucleoprotein (RNP) condensates such as stress granules (SGs) and P-bodies (PBs) where lncRNAs can attract proteins and RNAs (5). Accumulation of proteins and RNAs is a crucial event driving the formation of SGs and PBs via phase separation (4, 6, 7).…”

Computational tools to study RNA-protein complexes

“…Added challenges in the determination of structures of protein-RNA complexes include the recognition of RNA sequences of optimal size that will bind the protein specifically and stably and the inherent flexibility of such regions which can affect structural stability and structure determination efforts. The inherent diversity of RNA structures and proteins and the presence of intrinsically disordered regions presents an enormous challenge to the area as well (Dyson, 2012;Ottoz and Berchowitz, 2020;Vandelli et al, 2022). The cost and effort to experimentally capture and measure strengths of all biologically important RNA-protein complexes is challenging due to these unique complexities.…”