Accurate model of liquid–liquid phase behavior of intrinsically disordered proteins from optimization of single-chain properties

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(44)

Published: Oct. 29, 2021

Significance Cells may compartmentalize proteins via a demixing process known as liquid–liquid phase separation (LLPS), which is often driven by intrinsically disordered (IDPs) and regions. Protein condensates arising from LLPS develop into insoluble protein aggregates, in neurodegenerative diseases cancer. Understanding the of formation, dissolution, aging requires models that accurately capture underpinning interactions at residue level. In this work, we leverage data biophysical experiments on IDPs dilute solution to sequence-dependent model predicts conformational behavior diverse unrelated sequences with good accuracy. Using model, gain insight coupling between chain compaction propensity.

Language: Английский

---

Extreme dynamics in a biomolecular condensate

Nature, Journal Year: 2023, Volume and Issue: 619(7971), P. 876 - 883

Published: July 19, 2023

Language: Английский

---

Conformational Dynamics of Intrinsically Disordered Proteins Regulate Biomolecular Condensate Chemistry

Chemical Reviews, Journal Year: 2022, Volume and Issue: 122(6), P. 6719 - 6748

Published: Feb. 18, 2022

Motions in biomolecules are critical for biochemical reactions. In cells, many reactions executed inside of biomolecular condensates formed by ultradynamic intrinsically disordered proteins. A deep understanding the conformational dynamics proteins is therefore utmost importance but complicated diverse obstacles. Here we review emerging data on motions liquidlike condensates. We discuss how liquid-liquid phase separation modulates internal across a wide range time and length scales. further highlight intermolecular interactions that not only drive appear as key determinants changes aging human diseases. The provides framework future studies to reveal regulation condensate chemistry.

Language: Английский

---

Amyloid formation as a protein phase transition

Nature Reviews Physics, Journal Year: 2023, Volume and Issue: 5(7), P. 379 - 397

Published: June 27, 2023

Language: Английский

---

Improved predictions of phase behaviour of intrinsically disordered proteins by tuning the interaction range

Open Research Europe, Journal Year: 2023, Volume and Issue: 2, P. 94 - 94

Published: Jan. 17, 2023

The formation and viscoelastic properties of condensates intrinsically disordered proteins (IDPs) is dictated by amino acid sequence solution conditions. Because the involvement biomolecular in cell physiology disease, advancing our understanding relationship between protein phase separation (PS) may have important implications formulation new therapeutic hypotheses. Here, we present CALVADOS 2, a coarse-grained model IDPs that accurately predicts conformational propensities to undergo PS for diverse sequences In particular, systematically study effect varying range nonionic interactions use findings improve temperature scale model. We further optimize residue-specific parameters against experimental data on 55 proteins, while also leveraging 70 hydrophobicity scales from literature avoid overfitting training data. Extensive testing shows chain compaction propensity length charge patterning, as well at different temperatures salt concentrations.

Language: Английский

---

The interface of condensates of the hnRNPA1 low-complexity domain promotes formation of amyloid fibrils

Nature Chemistry, Journal Year: 2023, Volume and Issue: 15(10), P. 1340 - 1349

Published: Sept. 25, 2023

The maturation of liquid-like protein condensates into amyloid fibrils has been associated with several neurodegenerative diseases. However, the molecular mechanisms underlying this liquid-to-solid transition have remained largely unclear. Here we analyse formation mediated by condensation low-complexity domain hnRNPA1, a involved in amyotrophic lateral sclerosis. We show that phase separation and fibrillization are connected but distinct processes modulated different regions sequence. By monitoring spatial temporal evolution demonstrate does not occur homogeneously inside droplets is promoted at interface condensates. further coating surfactant molecules inhibits fibril formation. Our results reveal biomolecular hnRNPA1 promotes formation, therefore suggesting interfaces as potential novel therapeutic target against aberrant amyloids condensation.

Language: Английский

---

Biomolecular condensates can both accelerate and suppress aggregation of α-synuclein

Science Advances, Journal Year: 2022, Volume and Issue: 8(48)

Published: Dec. 2, 2022

Biomolecular condensates present in cells can fundamentally affect the aggregation of amyloidogenic proteins and play a role regulation this process. While liquid-liquid phase separation by themselves act as an alternative nucleation pathway, interaction partly disordered aggregation-prone with preexisting that localization centers could be far more general mechanism altering their behavior. Here, we show so-called host biomolecular both accelerate slow down amyloid formation. We study protein α-synuclein two truncated variants presence three types composed nonaggregating peptides, RNA, or ATP. Our results demonstrate markedly speed up formation when localize to interface. However, also significantly suppress sequestering stabilizing proteins, thereby providing living possible protection against

Language: Английский

---

Spatiotemporal modulations in heterotypic condensates of prion and α-synuclein control phase transitions and amyloid conversion

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: March 3, 2022

Biomolecular condensation via liquid-liquid phase separation of proteins and nucleic acids is associated with a range critical cellular functions neurodegenerative diseases. Here, we demonstrate that complex coacervation the prion protein α-synuclein within narrow stoichiometry results in formation highly dynamic, reversible, thermo-responsive liquid droplets domain-specific electrostatic interactions between positively-charged intrinsically disordered N-terminal segment acidic C-terminal tail α-synuclein. The addition RNA to these coacervates yields multiphasic, vesicle-like, hollow condensates. Picosecond time-resolved measurements revealed presence transient nanoclusters are stable on nanosecond timescale can undergo breaking-and-making slower timescales giving rise liquid-like behavior mesoscopic regime. liquid-to-solid transition drives rapid conversion into heterotypic amyloids. Our suggest synergistic prion-α-synuclein condensates provide mechanistic underpinnings their physiological role overlapping neuropathological features.

Language: Английский

---

Global Structure of the Intrinsically Disordered Protein Tau Emerges from Its Local Structure

JACS Au, Journal Year: 2022, Volume and Issue: 2(3), P. 673 - 686

Published: March 1, 2022

The paradigmatic disordered protein tau plays an important role in neuronal function and neurodegenerative diseases. To disentangle the factors controlling balance between functional disease-associated conformational states, we build a structural ensemble of K18 fragment containing four pseudorepeat domains involved both microtubule binding amyloid fibril formation. We assemble 129-residue-long chains with atomic detail from extensive library constructed molecular dynamics simulations. introduce reweighted hierarchical chain growth (RHCG) algorithm that integrates experimental data reporting on local structure into assembly process systematic manner. By combining Bayesian refinement importance sampling, obtain well-defined ensembles overcome problem exponentially varying weights integrative modeling long-chain polymeric molecules. resulting capture nuclear magnetic resonance (NMR) chemical shift J-coupling measurements. Without further fitting, achieve very good agreement measurements NMR residual dipolar couplings. measures global such as single-molecule Förster energy transfer (FRET) efficiencies is improved by refinement. comparing wild-type mutant ensembles, show pathogenic single-point P301L, P301S, P301T mutations population turn-like conformations microtubule-bound state to extended fibrils. RHCG thus provides us atomically detailed view equilibrium aggregation-prone states K18, demonstrates characteristics this intrinsically emerge its structure.

Language: Английский

---

Liquid–Liquid Phase Separation Modifies the Dynamic Properties of Intrinsically Disordered Proteins

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(19), P. 10548 - 10563

Published: May 5, 2023

Liquid–liquid phase separation of flexible biomolecules has been identified as a ubiquitous phenomenon underlying the formation membraneless organelles that harbor multitude essential cellular processes. We use nuclear magnetic resonance (NMR) spectroscopy to compare dynamic properties an intrinsically disordered protein (measles virus NTAIL) in dilute and dense phases at atomic resolution. By measuring 15N NMR relaxation different field strengths, we are able characterize dynamics crowded conditions amplitude timescale motional modes those present organelle. Although local backbone conformational sampling appears be largely retained, occurring on all detectable timescales, including librational, dihedral angle segmental, chainlike motions, considerably slowed down. Their relative amplitudes also drastically modified, with slower, chain-like motions dominating profile. In order provide additional mechanistic insight, performed extensive molecular simulations under self-crowding concentrations comparable found liquid phase. Simulation broadly reproduces impact condensed both free energy landscape kinetic interconversion between states. particular, experimentally observed reduction fastest component correlates higher levels intermolecular contacts or entanglement simulations, reducing space available this mode strongly conditions.

Language: Английский

---