Jul 2026· Current Opinion in Structural Biology· Vol 99, pp.
103309
· 0 citations· 47 references
Medicine
TL;DR
This review discusses how features of protein sequence, such as amino acid composition, interaction motifs, and post-translational modifications, influence condensate aging and highlights how interactions with RNA and lipid membranes modulate condensate behavior by altering interaction networks and interfacial properties.
Abstract
Biomolecular condensates play key roles in the cell by organizing and regulating important biochemical processes, including transcriptional regulation, RNA metabolism, ribosome biogenesis, and stress responses. While these assemblies are typically dynamic, some can undergo time-dependent aging into solid assemblies, which in certain cases has been linked to pathologies including neurodegenerative diseases. In this review, we focus on the mechanisms that drive condensate aging. In particular, we discuss how features of protein sequence, such as amino acid composition, interaction motifs, and post-translational modifications, influence condensate aging. We further highlight how interactions with RNA and lipid membranes modulate condensate behavior by altering interaction networks and interfacial properties.
Biomolecular condensates are dynamic membraneless organelles composed of proteins and RNAs that assemble through multivalent interactions and provide cells with powerful means to regulate gene expression in space and time. Different epitranscriptomic marks such as m6A, m1A, and m5C can reshape RNA structure—binding interfaces and multivalency and, in this manner, tuning which transcripts nucleate or partition into specific condensates and influencing their material state. This review summarizes how individual RNA modifications and their associated proteins regulate the formation and function of BMCs such as stress granules, P-bodies, nuclear bodies and disease-linked condensates in cancer and neurodegeneration. It highlights emerging concepts of combinatorial “epitranscriptomic codes” and bidirectional feedback between condensates and RNA-modifying enzymes and discusses the current experimental and technical gaps that still limit our understanding of modification crosstalk and condensate topology.
Y. Sprecher, M. Sevilla-Sharon, S. Moshitch-Moshkovitz· Genes· 0 citations
G3BP1 is a central scaffold of stress granules (SGs). Upon cellular stress, G3BP1 forms complex coacervates with translationally repressed mRNAs and recruits multiple RNA-binding proteins to form reversible biomolecular condensates. Persistent SGs are linked to age-dependent dynamical arrest and impaired disassembly. Here, we employ active and passive nanoscale rheology with optical tweezers to show that G3BP1 condensates evolve from being dominantly viscous fluids to dynamically arrested network glasses characterized by nanoscale caging and elastic memory. Integrating atomistic and coarse-grained simulations with experiments, we find that electrostatic interactions between the oppositely charged intrinsically disordered regions drive condensate ageing. RNA modulates these interactions in a length-and structure-dependent manner, delaying dynamic arrest, whereas Caprin-1 binding to the NTF2L domain has little effect. Together, these findings reveal how competing inter-IDR and IDR–RNA interactions govern condensate ageing and material-state transitions. The findings have broader implications for the regulation of SG dynamics in cells.
SUMMARY Liquid–liquid phase separation (LLPS) drives the formation of biomolecular condensates, a conserved phenomenon across eukaryotes. This process governs diverse cellular programs, from stress response and morphogenesis to disease pathology. Over the past two decades, the regulatory impact of biomolecular condensates in fungal biology has become increasingly recognized. In this review, we examine the fundamental molecular mechanisms driving LLPS, evaluate the current evidence for LLPS in macromolecular organization and cellular regulation in fungi, and outline the tools employed to study this phenomenon. Lastly, we highlight the challenges of bridging the gap between the in vitro behavior of biomolecular condensates and their complex regulatory functions in vivo within fungal biology.
Emma E Blackburn, Xiaorong Lin· Microbiology and Molecular B...· 0 citations
A review of the latest breakthroughs in the structural classification of G4s reveals the multifaceted physiological and pathological functions of G4‐driven condensates, including chromatin organization, assembly of stress granules and paraspeckles, abnormal transcriptional activation, telomere maintenance, neurodegenerative disease‐associated protein aggregation, and viral inclusion body formation.
Wenmeng Wang, Qingqing Xu, Yuxin Zhang et al.· Advancement of science· 0 citations
The current literature is summarized and biomolecular condensates are described as key regulators of protein misfolding and aggregation and the importance of the local milieu in determining aggregation outcomes is highlighted.
Emre Pekbilir, Dorothee Dormann· Current Opinion in Structura...· 0 citations
This work performs equilibrium and non-equilibrium residue-resolution molecular dynamics simulations to determine how RNA and heterotypic protein interactions regulate the pathological hardening of multicomponent FUS-containing condensates inspired by stress-granule composition.
Eduardo Pedraza, Óscar Rebato, A. Feito et al.· bioRxiv· 0 citations
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