Sequence-specific interactions determine viscoelasticity and aging dynamics of protein condensates

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

Published: April 6, 2023

Abstract Biomolecular condensates are viscoelastic materials. Here, we report results from investigations into molecular-scale determinants of sequence-encoded and age-dependent viscoelasticity formed by prion-like low-complexity domains (PLCDs). The terminally viscous forms PLCD Maxwell fluids. Measured moduli these reproducible using a Rouse-Zimm model that accounts for the network-like organization engendered reversible physical crosslinks among PLCDs in dense phase. Measurements computations show strengths aromatic inter-sticker interactions determine sequence-specific amplitudes elastic as well timescales over which properties dominate. also undergo aging on timescales. This is driven mutations to spacer residues weaken metastability phases. accompanied disorder-to-order transitions, leading formation non-fibrillar, beta-sheet-containing, semi-crystalline, elastic, Kelvin-Voigt solids. Our suggest sequence grammars, refer identities stickers versus spacers PLCDs, have evolved afford control metastabilities fluid phases condensates. selection can, some cases, render barriers conversion metastable fluids globally stable solids be insurmountable functionally relevant

Language: Английский

---

Biomolecular condensates with complex architectures via controlled nucleation

Nature Chemical Engineering, Journal Year: 2024, Volume and Issue: unknown

Published: June 10, 2024

Language: Английский

---

An RNA condensate model for the origin of life

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169124 - 169124

Published: April 1, 2025

The RNA World hypothesis predicts that self-replicating RNAs evolved before DNA genomes and coded proteins. Despite widespread support for the World, have yet to be identified in a natural context, leaving key 'missing link' this explanation of origin life. Inspired by recent work showing condensates charged polymers are capable catalyzing chemical reactions, we consider catalytic condensate as candidate RNA. Specifically, propose short, low-complexity formed templated polymerization. Because properties depend on sequences, with improved polymerization demixing capacity would amplified, leading 'condensate chain reaction' evolution selection. Many needed been realized experimentally studies our predictions could tested current experimental theoretical tools. Our theory addresses central problems origins life: (i) compartmentalization, (ii) error threshold accuracy replication, (iii) free energy cost maintaining an information-rich population replicating polymers. Furthermore, note extant nucleolus appears satisfy many requirements evolutionary relic model propose. More generally, suggest future life benefit from condensate-centric biophysical models evolution.

Language: Английский

---

Single fluorogen imaging reveals distinct environmental and structural features of biomolecular condensates

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

Published: Jan. 27, 2023

Abstract Biomolecular condensates are viscoelastic materials. Simulations predict that fluid-like condensations defined by spatially inhomogeneous organization of the underlying molecules. Here, we test these predictions using single-fluorogen tracking and super-resolution imaging. Specifically, leverage localization orientational preferences freely diffusing fluorogens solvatochromic effect whereby specific turned on in response to condensate microenvironments. We deployed three different probe microenvironments molecular protein-based condensates. The spatiotemporal resolution environmental sensitivity afforded imaging shows internal environments more hydrophobic than coexisting dilute phases. Molecules within organized a manner, this gives rise slow-moving nanoscale clusters coexist with fast-moving Fluorogens localize preferentially interface help us map their distinct features. Our findings provide structural dynamical basis for viscoelasticity

Language: Английский

---

Ribonucleotide synthesis by NME6 fuels mitochondrial gene expression

The EMBO Journal, Journal Year: 2023, Volume and Issue: 42(18)

Published: July 13, 2023

Replication of the mitochondrial genome and expression genes it encodes both depend on a sufficient supply nucleotides to mitochondria. Accordingly, dysregulated nucleotide metabolism not only destabilises genome, but also affects its transcription. Here, we report that nucleoside diphosphate kinase, NME6, supplies mitochondria with pyrimidine ribonucleotides are necessary for transcription genes. Loss NME6 function leads depletion transcripts, as well destabilisation electron transport chain impaired oxidative phosphorylation. These deficiencies rescued by an exogenous ribonucleosides. Moreover, is required maintenance DNA when access cytosolic deoxyribonucleotides limited. Our results therefore reveal important role ribonucleotide salvage in gene expression.

Language: Английский

---

Tuning Material States and Functionalities of G-Quadruplex-Modulated RNA-Peptide Condensates

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(4), P. 2375 - 2385

Published: Jan. 23, 2023

RNA encodes sequence- and structure-dependent interactions to modulate the assembly properties of biomolecular condensates. G-quadruplexes (rG4s) formed by guanine-rich sequences can trigger formation liquid- or solid-like condensates that are involved in many aberrant phase transitions. However, exactly how rG4 motifs different transitions impart distinct material is unclear. Here, using oligonucleotides cationic peptides as model systems, we show RNA-peptide exhibit tunability over a wide spectrum via arising from folding/unfolding kinetics. rG4-containing strong pairwise attraction with tended form condensates, while their less-structured non-G4 mutants liquid-like droplets. We find coupling between dissociation RNA–peptide complex coacervation triggers solid-to-liquid transition prior complete unfolding rG4s. This points mechanism states rG4-modulated be finely tuned addition oligonucleotides, which have weak but dominant binding peptides. further tunable enhance aptamer compartmentalization cleavage reactions. Our results suggest emerge subtle changes contributing ways treat dysfunctional diseases insights into prebiotic compartmentalization.

Language: Английский

---

Vacuole dynamics and popping-based motility in liquid droplets of DNA

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 16, 2023

Abstract Liquid droplets of biomolecules play key roles in organizing cellular behavior, and are also technologically relevant, yet physical studies dynamic processes such have generally been lacking. Here, we investigate quantify the dynamics formation dilute internal inclusions, i.e., vacuoles, within a model system consisting liquid DNA ‘nanostar’ particles. When acted upon by DNA-cleaving restriction enzymes, these exhibit cycles appearance, growth, bursting vacuoles. Analysis vacuole growth shows their radius increases linearly time. Further, vacuoles pop reaching droplet interface, leading to motion driven osmotic pressure fragments captured vacuole. We develop that accounts for linear nature pressures associated with motility, describing diffusing fragments. The results illustrate complex non-equilibrium possible biomolecular condensates.

Language: Английский

---

Direct computations of viscoelastic moduli of biomolecular condensates

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

Published: June 13, 2024

facsimiles of biomolecular condensates are formed by different types intrinsically disordered proteins including prion-like low complexity domains (PLCDs). PLCD viscoelastic materials defined time-dependent, sequence-specific complex shear moduli. Here, we show that moduli can be computed directly using a generalization the Rouse model and information regarding intra- inter-chain contacts is extracted from equilibrium configurations lattice-based Metropolis Monte Carlo (MMC) simulations. The key ingredient generalized Zimm matrix compute MMC We two flavors matrices, one referred to as single-chain accounts only for intra-chain contacts, other collective model, interactions. systematically overestimates storage loss moduli, whereas reproduces measured with greater fidelity. However, in long time, low-frequency domain, mixture models proves most accurate. In line theory Rouse, find continuous distribution relaxation times exists condensates. single crossover frequency between dominantly elastic versus viscous behaviors influenced totality modes. Hence, our analysis suggests fluid-like best described Maxwell fluids. Finally, used solve an inverse problem obtain distributions underlie dynamics within

Language: Английский

---

Function moves biomolecular condensates in phase space

BioEssays, Journal Year: 2022, Volume and Issue: 44(5)

Published: March 3, 2022

Phase separation underlies the formation of biomolecular condensates. We hypothesize cellular processes that occur within condensates shape their structural features. use example transcription to discuss structure-function relationships in Various types transcriptional have been reported across evolutionary spectrum cell nucleus as well mitochondrial and bacterial nucleoids. In vitro vivo observations suggest activity influences supramolecular structure, which turn affects function. Condensate organization thus becomes driven by differences miscibility among DNA proteins machinery RNA transcripts they generate. These considerations are line with notion properties condensates, leading a dynamic, mutual interplay between structure function cell.

Language: Английский

---

Revealing nanoscale structure and interfaces of protein and polymer condensates via cryo-electron microscopy

Nanoscale, Journal Year: 2024, Volume and Issue: 16(35), P. 16706 - 16717

Published: Jan. 1, 2024

This study uses cryo-electron microscopy to reveal the distinct nanoscale structures within protein condensates, highlighting potential correlation between their internal organization and material properties.

Language: Английский

---