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

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Equilibrium mechanisms of self-limiting assembly

Reviews of Modern Physics, Journal Year: 2021, Volume and Issue: 93(2)

Published: June 11, 2021

Self-assembly is a ubiquitous process in synthetic and biological systems, broadly defined as the spontaneous organization of multiple subunits (e.g. macromolecules, particles) into ordered multi-unit structures. The vast majority equilibrium assembly processes give rise to two states: one consisting dispersed disassociated subunits, other, bulk-condensed state unlimited size. This review focuses on more specialized class self-limiting assembly, which describes resulting finite-size These systems pose generic basic question, how do thermodynamic involving non-covalent interactions between identical "measure" select size assembled structures? In this review, we begin with an introduction statistical mechanical framework for thermodynamics, use highlight key physical ingredients that ensure will terminate at finite dimensions. Then, introduce examples classify them within based broad categories: self-closing assemblies open-boundary assemblies. include well-known cases biology soft matter - micellization amphiphiles shell/tubule formation tapered well less widely known classes assemblies, such short-range attractive/long-range repulsive geometrically-frustrated For each these mechanisms, describe mechanisms size, potential limitations selection. Finally, discuss alternative draw contrasts size-control can achieve relative self-limitation equilibrium, single-species

Language: Английский

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Biomolecular condensates at sites of DNA damage: More than just a phase

DNA repair, Journal Year: 2021, Volume and Issue: 106, P. 103179 - 103179

Published: July 14, 2021

Protein recruitment to DNA break sites is an integral part of the damage response (DDR). Elucidation hierarchy and temporal order with which sensors as well repair signaling factors assemble around chromosome breaks has painted a complex picture tightly regulated macromolecular interactions that build specialized compartments facilitate maintenance genome integrity. While many underlying interactions, e.g. between damage-induced histone marks, can be explained by lock-and-key or induced fit binding models assuming fixed stoichiometries, structurally less defined such highly dynamic multivalent implicated in phase separation, also participate formation multi-protein assemblies genotoxic stress. Although much remains learned about these types cooperative their functional roles, rapidly growing interest material properties biomolecular condensates concepts from polymer chemistry soft matter physics understand biological processes at different scales holds great promises. Here, we discuss nuclear context integrity maintenance, highlighting potential clustered stoichiometric separation. Rather than viewing them opposing scenarios, combined effects balance structural specificity favorable physicochemical relevant for regulation function multilayered condensates.

Language: Английский

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Double-stranded RNA drives SARS-CoV-2 nucleocapsid protein to undergo phase separation at specific temperatures

Nucleic Acids Research, Journal Year: 2022, Volume and Issue: 50(14), P. 8168 - 8192

Published: July 24, 2022

Abstract Nucleocapsid protein (N-protein) is required for multiple steps in betacoronaviruses replication. SARS-CoV-2-N-protein condenses with specific viral RNAs at particular temperatures making it a powerful model deciphering RNA sequence specificity condensates. We identify two separate and distinct double-stranded, motifs (dsRNA stickers) that promote N-protein condensation. These dsRNA stickers are separately recognized by N-protein's binding domains (RBDs). RBD1 prefers structured sequences like the transcription-regulatory (TRS). RBD2 long stretches of dsRNA, independent sequence. Thus, RBDs interact stickers, these interactions impart droplet physical properties could support varied functions. Specifically, we find addition lowers condensation temperature dependent on tunes translational repression. In contrast sites critical sub-genomic (sg) generation gRNA compression. The density proximity to TRS-L/B associated levels generation. switch packaging likely mediated which generate particles recapitulate unit virion. SARS-CoV-2 can achieve biochemical complexity, performing functions same cytoplasm, minimal components based utilizing control interactions.

Language: Английский

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Deconstructing virus condensation

PLoS Pathogens, Journal Year: 2021, Volume and Issue: 17(10), P. e1009926 - e1009926

Published: Oct. 14, 2021

Viruses have evolved precise mechanisms for using the cellular physiological pathways their perpetuation. These virus-driven biochemical events must be separated in space and time from those of host cell. In recent years, granular structures, known over a century rabies virus, were shown to viral gene function named terms such as viroplasms, replication sites, inclusion bodies, or factories (VFs). More recently, these VFs liquid-like, sharing properties with membrane-less organelles driven by liquid-liquid phase separation (LLPS) process widely referred biomolecular condensation. Some best described examples structures come negative stranded RNA viruses, where micrometer size are formed toward end infectious cycle. We here discuss some basic principles LLPS connection several propose view, which integrates biochemistry underlying liquid-like organelles. this protein components gradually accumulate up critical point during infection is triggered. This yields an increase transcription that leads turn increased translation consequent growth initially condensates. According chemical behind separation, concentration increases condensate. A positive feedback cycle would thus generate crucial components, particular nucleoproteins polymerases, reach highest levels required genome replication. Progress understanding condensation exploration novel therapeutics. Furthermore, it provides insights into fundamentals regulation given virus transcription, requiring governed same principles.

Language: Английский

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Phase separation in viral infections

Trends in Microbiology, Journal Year: 2022, Volume and Issue: 30(12), P. 1217 - 1231

Published: July 25, 2022

Language: Английский

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Biological soft matter: intrinsically disordered proteins in liquid–liquid phase separation and biomolecular condensates

Essays in Biochemistry, Journal Year: 2022, Volume and Issue: 66(7), P. 831 - 847

Published: Nov. 9, 2022

Abstract The facts that many proteins with crucial biological functions do not have unique structures and processes are compartmentalized into the liquid-like biomolecular condensates, which formed via liquid–liquid phase separation (LLPS) surrounded by membrane, revolutionizing modern biology. These phenomena interlinked, as presence of intrinsic disorder represents an important requirement for a protein to undergo LLPS drives biogenesis numerous membrane-less organelles (MLOs). Therefore, one can consider these constituents new IDP–LLPS–MLO field. Furthermore, intrinsically disordered (IDPs), LLPS, MLOs represent clear link between molecular cellular biology soft matter condensed physics. Both IDP LLPS/MLO fields undergoing explosive development generate ever-increasing mountain data. data provide answers so long-standing questions it is difficult imagine in very recent past, scientists biologists operated without taking revolutionary concepts account. goal this essay deliver comprehensive review field but brief rather subjective outline some developments exciting fields.

Language: Английский

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Overcoming Disordered Preaggregation in Liquid State for Highly Efficient Organic Solar Cells Printed from Nonhalogenated Solvents

Advanced Energy Materials, Journal Year: 2023, Volume and Issue: 13(9)

Published: Jan. 15, 2023

Abstract The current power conversion efficiencies of laboratory‐sized organic solar cells (OSCs), based on the spin‐coating process with halogenated solvents, have exceeded 19%. Environmentally friendly printing is needed to bridge gap between laboratory and industrialization by being compatible roll‐to‐roll large‐area production. Here, molecular design rules are revealed for enhancing green potential state‐of‐the‐art photovoltaic martial systems investigating detailed structure formation dynamic key determining factors. By comparing two model D18:Y6 D18:BTP‐eC9, it found that disordered preaggregation in liquid state can result over‐sized domains reduced crystallinity orientation, which significantly limits device performance. systematically tuning length inner alkyl side chains multiple Y‐series materials, authors demonstrate side‐chain engineering effectively supress detrimental during environmentally process, leading enhanced crystallization preferential faceon more efficient exciton dissociation charge carrier transport, finally high upscaling potential. work provides deeper insights into dynamics toward production OSCs.

Language: Английский

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Co‐opted cytosolic proteins form condensate substructures within membranous replication organelles of a positive‐strand RNA virus

New Phytologist, Journal Year: 2024, Volume and Issue: 243(5), P. 1917 - 1935

Published: March 21, 2024

Summary Positive‐strand RNA viruses co‐opt organellar membranes for biogenesis of viral replication organelles (VROs). Tombusviruses also pro‐viral cytosolic proteins to VROs. It is currently not known what type molecular organization keeps co‐opted sequestered within membranous In this study, we employed tomato bushy stunt virus (TBSV) and carnation Italian ringspot (CIRV) – Nicotiana benthamiana pathosystems identify biomolecular condensate formation in We show that TBSV p33 the CIRV p36 sequester glycolytic fermentation enzymes unique substructures associated with find form droplets vitro driven by intrinsically disordered region. The protein organizes partitioning host into droplets. VRO‐associated condensates are critical local adenosine triphosphate production support energy replication. endoplasmic reticulum actin filaments meshworks around VRO condensates, contributing composition structure. propose p33/p36 organize liquid–liquid phase separation concentrated Overall, demonstrate subverted co‐exist functions. induce connect two

Language: Английский

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A phage nucleus-associated RNA-binding protein is required for jumbo phage infection

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(8), P. 4440 - 4455

Published: March 30, 2024

Abstract Large-genome bacteriophages (jumbo phages) of the proposed family Chimalliviridae assemble a nucleus-like compartment bounded by protein shell that protects replicating phage genome from host-encoded restriction enzymes and DNA-targeting CRISPR-Cas nucleases. While nuclear provides broad protection against host nucleases, it necessitates transport mRNA out for translation ribosomes, specific proteins into to support DNA replication transcription. Here, we identify conserved shell-associated term Chimallin C (ChmC), which adopts nucleic acid-binding fold, binds RNA with high affinity in vitro, mRNAs infected cells. ChmC also forms phase-separated condensates vitro. Targeted knockdown using mRNA-targeting dCas13d results accumulation phage-encoded nucleus, reduces production, compromises virion assembly. Taken together, our data show plays crucial roles viral life cycle, potentially facilitating translocation through promote production development.

Language: Английский

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