Aug 2026· Current Opinion in Structural Biology· Vol 101, pp.
103355
· 0 citations· 73 references
Medicine
TL;DR
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.
Abstract
Protein aggregation is a hallmark in several neurodegenerative diseases, in which proteins assemble into structurally diverse misfolded states, ranging from amorphous aggregates to amyloid fibrils. Several aggregation-prone proteins can undergo phase separation to form biomolecular condensates, creating distinct chemical environments compared to the surrounding dilute phase. These environments dictate protein conformations, interaction networks, and free energy landscapes, thereby modulating aggregation pathways. Notably, condensates exert dual and context-dependent effects: they can promote aggregation by stabilizing misfolded intermediates and facilitating assembly, or they can suppress aggregation by buffering interactions and retaining proteins. Here, we summarize the current literature and describe biomolecular condensates as key regulators of protein misfolding and aggregation and highlight the importance of the local milieu in determining aggregation outcomes.
Macromolecular crowding can reshape the conformational landscapes of intrinsically disordered and marginally stable proteins linked to neurodegeneration, enriching aggregation-prone states and changing how nucleation begins. Crowding can also promote liquid-liquid phase separation, leading to condensates that concentrate proteins, reshape interaction networks, and in some cases promote liquid-to-solid transitions into amyloid assemblies. This crowding-liquid-liquid phase separation-aggregation continuum may help explain why dilute solution assays often fail to capture the mechanisms that operate in cells. Crowding-aware structural biology, including in-cell nuclear magnetic resonance, cryo-electron microscopy of condensates, single-molecule methods, and thermodynamic-kinetic modelling, will be important for resolving physiologically relevant intermediates. From a therapeutic perspective, targeting condensate properties and early oligomeric states, rather than focussing only on mature fibrils, may offer new ways to limit pathogenic aggregation.
Tejas Nikam, Shashi Prakash Patel, S. Saraf et al.· Current Opinion in Structura...· 1 citation
This work investigates how protein folding landscapes are altered inside condensates, using the protein α-helix as a model folded domain and develops a chemically specific, residue-resolution model for quantification of α-helical folding and applies it to characterize diverse helices within condensates of varying physicochemical properties.
Nathaniel Hess, Jerelle A. Joseph· Journal of the American Chem...· 0 citations
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.
Rebecca J. Thrush, Francesco A. Aprile· Current Opinion in Structura...· 0 citations
Stress granules are multicomponent biomolecular condensates whose aberrant ageing has been implicated in numerous neurodegenerative diseases. Although their composition is known to influence condensate properties, the molecular principles linking composition to structural maturation remain poorly understood. Here, we perform 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. We show that diverse compositional changes—including RNA concentration, heterotypic protein partitioning, interfacial enrichment of G3BP1, and charged peptide recruitment—reshape condensate organization through distinct molecular mechanisms. Despite these different modes of action, all converge on a common physical principle: modulation of the local clustering and persistence of contacts between low-complexity aromatic-rich kinked segments (LARKS) governs the nucleation and accumulation of long-lived intermolecular cross-β-sheet structures. Intermediate RNA concentrations enhance condensate density and promote LARKS contacts, whereas high RNA levels, heterotypic interactions, and interfacial coating reduce their availability and delay ageing. Our results establish a unified molecular framework linking condensate composition, internal organization and ageing. This framework provides mechanistic insight into the regulation of multicomponent condensate material properties and suggests general design principles for modulating their pathological aggregation.
Eduardo Pedraza, Óscar Rebato, A. Feito et al.· bioRxiv· 0 citations
Tau is an intrinsically disordered protein critical to the nervous system, and its aberrant aggregation is a key pathogenic factor in multiple diseases. However, the underlying triggers remain elusive. Here, using in vitro reconstitution and high-resolution imaging, we identify tRNA as a major inducer of tau aberrant aggregation. Mechanistically, tRNA drives the formation of fibrillar aggregates from tau liquid–liquid phase separation (LLPS) condensates via electrostatic interactions, which over time can evolve into pathological aggregates. Moreover, captopril (CAP) effectively inhibits both general and tRNA-induced tau aggregation, positioning CAP as a potential therapeutic candidate. This work offers an avenue for treating aberrant phase separation-induced tau aggregation using small-molecule compounds.
Boru Peng, Quan Deng, Xiaohua Zhu et al.· Langmuir· 0 citations
Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) lack stable tertiary structures yet perform essential roles in cellular signaling, molecular recognition, transcriptional regulation, and biomolecular assembly. Their conformational flexibility enables functional adaptability but also increases susceptibility to aberrant intermolecular interactions and protein aggregation. Unlike folded proteins, aggregation in IDPs arises from transient conformational ensembles that expose cryptic aggregation-prone regions (APRs), facilitating oligomerization and fibril formation under specific cellular and environmental conditions. Several studies have further established a mechanistic relationship between intrinsic disorder, liquid–liquid phase separation (LLPS), and pathological aggregation, where dynamic condensates can undergo maturation into irreversible amyloid-like assemblies. These transitions are strongly influenced by sequence grammar, charge distribution, aromatic residue patterning, post-translational modifications, molecular crowding, and proteostasis regulation. This mini-review summarizes the molecular principles governing aggregation in disordered systems, with emphasis on conformational ensemble dynamics, disorder-to-order transitions, and the interplay between LLPS and fibrillization. The review further discusses computational approaches used to predict aggregation propensity in IDRs, including classical physicochemical predictors, ensemble-aware simulations, molecular dynamics frameworks, and emerging protein language model-based methods. Further, integration of artificial intelligence, structural biophysics, and multiscale modeling have substantially improved understanding of disorder-driven aggregation pathways. Collectively, these findings support a unified framework in which sequence composition, conformational heterogeneity, and cellular environment cooperatively regulate functional assembly and pathological aggregation in intrinsically disordered proteins.
Rahul Kaushik, Suyong Re· Frontiers in Biophysics· 1 citation