Deciphering how naturally occurring sequence features impact the phase behaviours of disordered prion-like domains

Nature Chemistry, Journal Year: 2021, Volume and Issue: 14(2), P. 196 - 207

Published: Dec. 20, 2021

Language: Английский

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Biomolecular Condensates in the Nucleus

Trends in Biochemical Sciences, Journal Year: 2020, Volume and Issue: 45(11), P. 961 - 977

Published: July 17, 2020

Language: Английский

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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

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Biomolecular Condensates and Cancer

Cancer Cell, Journal Year: 2021, Volume and Issue: 39(2), P. 174 - 192

Published: Jan. 9, 2021

Language: Английский

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Phase Transitions of Associative Biomacromolecules

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(14), P. 8945 - 8987

Published: March 7, 2023

Multivalent proteins and nucleic acids, collectively referred to as multivalent associative biomacromolecules, provide the driving forces for formation compositional regulation of biomolecular condensates. Here, we review key concepts phase transitions aqueous solutions specifically that include folded domains intrinsically disordered regions. The these systems come under rubric coupled segregative transitions. underlying processes are presented, their relevance condensates is discussed.

Language: Английский

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Intrinsically disordered protein regions and phase separation: sequence determinants of assembly or lack thereof

Emerging Topics in Life Sciences, Journal Year: 2020, Volume and Issue: 4(3), P. 307 - 329

Published: Oct. 20, 2020

Intrinsically disordered protein regions (IDRs) — that do not fold into a fixed three-dimensional structure but instead exist in heterogeneous ensemble of conformations have recently entered mainstream cell biology the context liquid–liquid phase separation (LLPS). IDRs are frequently found to be enriched phase-separated compartments. Due this observation, presence an IDR is assumed diagnostic its ability separate. In review, we clarify role biological assembly and explore physical principles through which amino acids can confer attractive molecular interactions underlie separation. While some will robustly drive separation, many others not. We emphasize rather than ‘disorder' driving multivalency drives As such, whether or region capable depend on chemistry encoded within acid sequence. Consequently, in-depth understanding prerequisite make informed inferences how why may involved or, more generally, protein-mediated intermolecular interactions.

Language: Английский

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Sequence-encoded and composition-dependent protein-RNA interactions control multiphasic condensate morphologies

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Feb. 8, 2021

Multivalent protein-protein and protein-RNA interactions are the drivers of biological phase separation. Biomolecular condensates typically contain a dense network multiple proteins RNAs, their competing molecular play key roles in regulating condensate composition structure. Employing ternary system comprising prion-like polypeptide (PLP), arginine-rich (RRP), RNA, we show that competition between PLP RNA for single shared partner, RRP, leads to RNA-induced demixing PLP-RRP into stable coexisting phases-homotypic heterotypic RRP-RNA condensates. The morphology these biphasic (non-engulfing/ partial engulfing/ complete engulfing) is determined by RNA-to-RRP stoichiometry hierarchy intermolecular interactions, providing glimpse broad range multiphasic patterns accessible Our findings provide minimal set physical rules govern spatial organization multicomponent biomolecular

Language: Английский

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Phase-separating RNA-binding proteins form heterogeneous distributions of clusters in subsaturated solutions

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(28)

Published: July 5, 2022

Macromolecular phase separation is thought to be one of the processes that drives formation membraneless biomolecular condensates in cells. The dynamics are follow tenets classical nucleation theory, and, therefore, subsaturated solutions should devoid clusters with more than a few molecules. We tested this prediction using vitro biophysical studies characterize phase-separating RNA-binding proteins intrinsically disordered prion-like domains and domains. Surprisingly, direct contradiction expectations from we find characterized by presence heterogeneous distributions clusters. cluster sizes, which dominated small species, shift continuously toward larger sizes as protein concentrations increase approach saturation concentration. As result, many encompass tens hundreds molecules, while less 1% mesoscale species several hundred nanometers diameter. supersaturated strongly coupled via sequence-encoded interactions. also can decoupled solutes well specific sets mutations. Our findings, concordant predictions for associative polymers, implicate an interplay between networks sequence-specific solubility-determining interactions that, respectively, govern above occurs.

Language: Английский

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SON and SRRM2 are essential for nuclear speckle formation

eLife, Journal Year: 2020, Volume and Issue: 9

Published: Oct. 23, 2020

Nuclear speckles (NS) are among the most prominent biomolecular condensates. Despite their prevalence, research on function of NS is virtually restricted to colocalization analyses, since an organizing core, without which cannot form, remains unidentified. The monoclonal antibody SC35, raised against a spliceosomal extract, frequently used mark NS. Unexpectedly, we found that this was mischaracterized and main target SC35 mAb SRRM2, spliceosome-associated protein sharply localizes Here show that, core likely formed by SON depletion leads only partial disassembly NS, while co-depletion SRRM2 or in cell-line where intrinsically disordered regions (IDRs) genetically deleted, near-complete dissolution This work, therefore, paves way study role under diverse physiological stress conditions.

Language: Английский

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Programmable viscoelasticity in protein-RNA condensates with disordered sticker-spacer polypeptides

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Nov. 16, 2021

Abstract Liquid-liquid phase separation of multivalent proteins and RNAs drives the formation biomolecular condensates that facilitate membrane-free compartmentalization subcellular processes. With recent advances, it is becoming increasingly clear are network fluids with time-dependent material properties. Here, employing microrheology optical tweezers, we reveal molecular determinants govern viscoelastic behavior formed by Arg/Gly-rich sticker-spacer polypeptides RNA. These behave as Maxwell an elastically-dominant rheological response at shorter timescales a liquid-like longer timescales. The viscous elastic regimes these can be tuned polypeptide RNA sequences well their mixture compositions. Our results establish quantitative link between sequence- structure-encoded interactions microscopic scale properties resulting mesoscale, enabling route to systematically probe rationally engineer programmable mechanics.

Language: Английский

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