Decoding phase separation of prion-like domains through data-driven scaling laws

eLife, Journal Year: 2025, Volume and Issue: 13

Published: Feb. 12, 2025

Proteins containing prion-like low complexity domains (PLDs) are common drivers of the formation biomolecular condensates and prone to misregulation due amino acid mutations. Here, we exploit accuracy our residue-resolution coarse-grained model, Mpipi, quantify impact mutations on stability 140 PLD mutants from six proteins (hnRNPA1, TDP43, FUS, EWSR1, RBM14, TIA1). Our simulations reveal existence scaling laws that range change in critical solution temperature PLDs as a function number type sequence These rules consistent with physicochemical properties extend across entire family tested, suggesting can be used tools predict changes condensates. work offers quantitative lens into how emergent behavior solutions vary response single molecules.

Language: Английский

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Backbone interactions and secondary structures in phase separation of disordered proteins

Biochemical Society Transactions, Journal Year: 2024, Volume and Issue: 52(1), P. 319 - 329

Published: Feb. 13, 2024

Intrinsically disordered proteins (IDPs) are one of the major drivers behind formation and characteristics biomolecular condensates. Due to their inherent flexibility, backbones IDPs significantly exposed, rendering them highly influential susceptible phase separation. In densely packed condensates, exposed have a heightened capacity interact with neighboring protein chains, which might lead strong coupling between secondary structures separation further modulate subsequent transitions such as aging fibrillization. this mini-review, we provide an overview backbone-mediated interactions within condensates underscore importance in We focus on recent advances experimental techniques molecular dynamics simulation methods for probing exploring roles backbone involving IDPs.

Language: Английский

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Biomolecular Condensates Can Enhance Pathological RNA Clustering

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 13, 2024

Intracellular aggregation of repeat expanded RNA has been implicated in many neurological disorders. Here, we study the role biomolecular condensates on irreversible clustering. We find that physiologically relevant, and disease-associated RNAs spontaneously undergo an age-dependent percolation transition inside multi-component protein-nucleic acid to form nanoscale clusters. Homotypic clusters drive emergence multiphasic condensate structures, with RNA-rich solid core surrounded by RNA-depleted fluid shell. The timescale clustering, which accompanies a liquid-to-solid condensates, is determined sequence features, stability secondary structure, length. Importantly, G3BP1, scaffold stress granules, introduces heterotypic buffering homotypic RNA-RNA interactions impedes intra-condensate clustering ATP-independent manner. Our work suggests can act as sites for aggregation. It also highlights functional RNA-binding proteins suppressing aberrant phase transitions.

Language: Английский

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Dynamically arrested condensate fusion creates complex structures with varying material properties

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 15, 2024

Abstract The cell nucleus and cytosol contain numerous biomolecular condensates which dynamically reshape, fuse split to accomplish precise compartmentalization of the material. While it has been observed that some rapidly coalesce, others only attach each other, or do not establish persistent interactions over time. Here, we explain these observations through optical tweezers Molecular Dynamics simulations focusing on two condensate-forming, RNA-binding proteins—FUS G3BP1—strongly involved in RNA metabolism stress responses. We find fusion pure droplets formed by proteins can give rise multiphase single-component exhibiting notably different densities, architectures, material properties. Such behaviour is dictated relative timescales condensate protein internal mixing. A critical parameter controlling this interplay extent ageing display; e.g., their progressive hardening driven accumulation inter-protein β -sheet assemblies Strikingly, degrees fusing lead form diverse architectures including concentric drops two-sided condensates. Overall, our results highlight a mechanism, based temporal coupling between ageing, fusion, mixing rate, multiphasic structures with markedly properties, hence potentially distinct biological roles.

Language: Английский

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Direct Prediction of Intrinsically Disordered Protein Conformational Properties From Sequence

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: May 8, 2023

ABSTRACT Intrinsically disordered regions (IDRs) are ubiquitous across all domains of life and play a range functional roles. While folded generally well-described by single 3D structure, IDRs exist in collection interconverting states known as an ensemble. This structural heterogeneity means largely absent from the PDB, contributing to lack computational approaches predict ensemble conformational properties sequence. Here we combine rational sequence design, large-scale molecular simulations, deep learning develop ALBATROSS, model for predicting IDR dimensions ALBATROSS enables instantaneous prediction average at proteome-wide scale. is lightweight, easy-to-use, accessible both locally installable software package point-and-click style interface cloud. We first demonstrate applicability our predictors examining generalizability sequence-ensemble relationships IDRs. Then, leverage high-throughput nature characterize emergent biophysical behavior within between proteomes. Update previous version preprint reports updated network weights trained on simulations over 42,000 sequences. In addition, provide new colab notebooks that enable annotation minutes. All conclusions observations made versions 1 2 this manuscript remain true robust.

Language: Английский

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Design of intrinsically disordered protein variants with diverse structural properties

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 24, 2023

Intrinsically disordered proteins (IDPs) perform a wide range of functions in biology, suggesting that the ability to design IDPs could help expand repertoire with novel functions. Designing specific structural or functional properties has, however, been difficult, part because determining accurate conformational ensembles generally requires combination computational modelling and experiments. Motivated by recent advancements efficient physics-based models for simulations IDPs, we have developed general algorithm designing properties. We demonstrate power generating variants naturally occurring different levels compaction vary more than 100 fold their propensity undergo phase separation, even while keeping fixed amino acid composition. experimentally tested designs low-complexity domain hnRNPA1 find high accuracy our predictions, both terms single-chain separation. analyze sequence features determine changes separate an overall good agreement previous findings sequences. Our general, method enables sequences specified thus expands toolbox protein include also most flexible will enable whose exploit many afforded disorder.

Language: Английский

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Direct Prediction Of Intrinsically Disordered Protein Conformational Properties From Sequence

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: June 16, 2023

Abstract Intrinsically disordered regions (IDRs) are ubiquitous across all domains of life and play a range functional roles. While folded generally well-described by single 3D structure, IDRs exist in collection interconverting states known as an ensemble. This structural heterogeneity means largely absent from the PDB, contributing to lack computational approaches predict ensemble conformational properties sequence. Here we combine rational sequence design, large-scale molecular simulations, deep learning develop ALBATROSS, model for predicting IDR dimensions ALBATROSS enables instantaneous prediction average at proteome-wide scale. is lightweight, easy-to-use, accessible both locally installable software package point-and-click style interface cloud. We first demonstrate applicability our predictors examining generalizability sequence-ensemble relationships IDRs. Then, leverage high-throughput nature characterize emergent biophysical behavior within between proteomes.

Language: Английский

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Protein condensates in the the secretory pathway: Unraveling biophysical interactions and function

Biophysical Journal, Journal Year: 2024, Volume and Issue: 123(12), P. 1531 - 1541

Published: May 2, 2024

Language: Английский

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Reconciling competing models on the roles of condensates and soluble complexes in transcription factor function

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 22, 2024

Phase separation explains the exquisite spatial and temporal regulation of many biological processes, but role transcription factor-mediated condensates in gene is contentious, requiring head-to-head comparison competing models. Here, we focused on prototypical yeast factor Gcn4 assessed two models for activation, i.e., mediated via soluble complexes or transcriptional condensates. Both rely ability factors coactivators to engage multivalent interactions. Unexpectedly, found that propensity form homotypic does not correlate well with activity. Contrary prevailing models, binding DNA suppresses phase separation. Notably, coactivator subunit Med15 closely mirrored recruit into condensates, indicating these properties are intertwined cautioning against interpretation mutational data without comparisons. However, variants highest affinity do function as expected instead have activities reflect their abilities separate Med15. These therefore indeed cellular those attenuate Our results show can reconciling seemingly opposing implications other phase-separating systems.

Language: Английский

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Stress granule formation helps to mitigate neurodegeneration

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 11, 2023

Cellular stress pathways that inhibit translation initiation lead to transient formation of cytoplasmic RNA/protein complexes known as granules. Many the proteins found within granules and dynamics granule dissolution are implicated in neurodegenerative disease. Whether is protective or harmful conditions not known. To address this, we took advantage alphavirus protein nsP3, which selectively binds dimers central nucleator G3BP (

Language: Английский

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