Jul 2026· Frontiers in Biophysics· 1 citation· 48 references
TL;DR
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.
Abstract
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.
Peptide self-assembly and liquid-liquid phase separation (LLPS), often mediated by intrinsically disordered regions (IDRs), are natural mechanisms that translate protein molecular features into complex nano- and mesoscale architectures. Although the thermodynamics and kinetics of these processes are well understood, synthetic materials integrating both functionalities remain rare. Inspired by the conserved IDR-assembly domain (AD) architecture of amyloidogenic proteins, we hypothesized that modular recombinant constructs combining LLPS-capable IDRs with β-sheet-forming ADs could generate materials with tunable structural properties. To test this, we engineered a library of elastin-like polypeptides (ELPs) fused to amphiphilic anionic or cationic amyloidogenic peptides, enabling systematic investigation of how sequence parameters─including ELP length, AD charge, and hydrophilicity─and environmental conditions, including temperature, pH, and salt concentration, influence material behavior. Our results reveal links between molecular design and emergent multiscale structures, including micelles and vesicles embedded within coacervates. This work provides a framework for designing hybrid proteins coupling LLPS and self-assembly.
Yulia Shmidov, Li-Xin Fan, Max R. Ney et al.· Biomacromolecules· 0 citations
Protein self-interaction to form homodimers and higher-order homo-oligomers is a ubiquitous phenomenon fundamental to living organisms. Recent structural, system-level, and computational insights reveal that self-interacting proteins dictate the specificity, rewiring, and topological complexity of cellular signaling networks and macromolecular assemblies. Beyond their physiological roles, aberrant or dysregulated homotypic interactions disrupt cellular proteostasis, driving the formation of toxic non-native oligomers, pathological amyloid fibrillization, or aberrant liquid–liquid phase separation transitions linked to neurodegenerative and systemic diseases. This review provides a comprehensive overview of the state-of-the-art experimental methodologies, including proximity labeling, as well as the advanced computational frameworks, such as deep learning architectures and protein language models, used to map the structural dynamics of SIPs. Furthermore, we dissect the evolutionary trajectories of SIPs within protein–protein interaction networks, which are underpinned by dosage-balance constraints, and highlight their diverse functional advantages, ranging from allosteric modulation to biomolecular condensation. Finally, we summarize the molecular mechanisms linking pathological self-associations to human disorders, underscoring the emerging paradigm of targeting homotypic interfaces as a promising frontier for precision therapeutics.
Yuanxiao Gao, Wenyu Zhang, Guang Hu· International Journal of Mol...· 0 citations
Deletion analysis demonstrates that the N-proximal prion domain (Sup35N) of Sup35 is sufficient for chaperone-dependent prion propagation and that various regions of this domain show differential impacts on LLPS, amyloid aggregation, and prion inheritance.
A. Grizel, Natalia A. Gorsheneva, Ismat Jahan Anee et al.· International Journal of Mol...· 0 citations
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
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
Macromolecular crowding significantly influences protein folding, stability, and aggregation within cellular environments. Here, Cellular Retinoic Acid Binding Protein I (CRABP I), a highly stable β-barrel protein with low intrinsic aggregation propensity, was employed to investigate the concentration-dependent effects of PEG 1000 on temperature-assisted refolding. Structural, functional, and biological consequences of refolding were examined using spectroscopic, microscopic, rheological, ligand-binding, zeta potential, and in vivo analyses. Refolding in the absence of PEG produced soluble but structurally heterogeneous intermediates. In contrast, low PEG concentration promoted intermolecular protein-protein interactions, leading to amorphous aggregation, altered structural properties, reduced retinoic acid-binding activity, and enhanced oxidative stress and cellular damage in Drosophila melanogaster. Higher PEG concentrations suppressed aggregation and favoured structurally stabilized conformations with preserved ligand-binding function. These findings demonstrate that PEG 1000 acts as a concentration-dependent molecular switch governing the balance between aggregation and productive refolding of CRABP I.
Laxmipriya Prusty, Kalpanarani Dash, Monalisa Mishra et al.· International Journal of Bio...· 0 citations
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