Protein conformation and biomolecular condensates

Current Research in Structural Biology, Год журнала: 2022, Номер 4, С. 285 - 307

Опубликована: Янв. 1, 2022

Protein conformation and cell compartmentalization are fundamental concepts subjects of vast scientific endeavors. In the last two decades, we have witnessed exciting advances that unveiled conjunction these concepts. An avalanche studies highlighted central role biomolecular condensates in membraneless subcellular permits spatiotemporal organization regulation myriads simultaneous biochemical reactions macromolecular interactions. These also shown condensation, driven by multivalent intermolecular interactions, is mediated order-disorder transitions protein domain architecture. Conceptually, condensation a distinct level conformational landscape which collective folding large collections molecules takes place. Biomolecular arise physical process phase separation comprise variety bodies ranging from organelles to liquid solid-like conglomerates, spanning lengths mesoscopic clusters (nanometers) micrometer-sized objects. this review, summarize discuss recent work on assembly, composition, conformation, material properties, thermodynamics, regulation, functions bodies. We review conceptual framework for future dynamics condensed proteins cellular processes.

Язык: Английский

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Principles and functions of condensate modifying drugs

Frontiers in Molecular Biosciences, Год журнала: 2022, Номер 9

Опубликована: Ноя. 22, 2022

Biomolecular condensates are compartmentalized communities of biomolecules, which unlike traditional organelles, not enclosed by membranes. Condensates play roles in diverse cellular processes, dysfunctional many disease states, and often enriched classically "undruggable" targets. In this review, we provide an overview for how drugs can modulate condensate structure function phenotypically classifying them as dissolvers (dissolve condensates), inducers (induce localizers (alter localization the specific community members) or morphers physiochemical properties). We discuss growing list bioactive molecules that modifiers (c-mods), including small molecules, oligonucleotides, peptides. propose understanding mechanisms perturbation known c-mods will accelerate discovery a new class therapies difficult-to-treat diseases.

Язык: Английский

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Self-assembly coupled to liquid-liquid phase separation

PLoS Computational Biology, Год журнала: 2023, Номер 19(5), С. e1010652 - e1010652

Опубликована: Май 15, 2023

Liquid condensate droplets with distinct compositions of proteins and nucleic acids are widespread in biological cells. While it is known that such droplets, or compartments, can regulate irreversible protein aggregation, their effect on reversible self-assembly remains largely unexplored. In this article, we use kinetic theory solution thermodynamics to investigate the liquid-liquid phase separation structures well-defined sizes architectures. We find that, when assembling subunits preferentially partition into liquid robustness against traps maximum achievable assembly rates be significantly increased. particular, both range conditions leading productive corresponding increase by orders magnitude. analyze rate equation predictions using simple scaling estimates identify effects as a function relevant control parameters. These results may elucidate processes underlie normal cellular functions pathogenesis, suggest strategies for designing efficient bottom-up nanomaterials applications.

Язык: Английский

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Condensation Goes Viral: A Polymer Physics Perspective

Journal of Molecular Biology, Год журнала: 2023, Номер 435(16), С. 167988 - 167988

Опубликована: Янв. 26, 2023

The past decade has seen a revolution in our understanding of how the cellular environment is organized, where an incredible body work provided new insights into role played by membraneless organelles. These rapid advancements have been made possible increasing awareness peculiar physical properties that give rise to such bodies and complex biology enables their function. Viral infections are not extraneous this. Indeed, host cells, viruses can harness existing compartments or, even, induce formation ones. By hijacking machinery, these intracellular assist replication, assembly, packaging viral genome as well escape immune response. Here, we provide perspective on fundamental polymer physics concepts may help connect interpret different observed phenomena, ranging from condensation genomes phase separation multicomponent solutions. We complement discussion basis with description biophysical methods quantitative for testing developing theoretical computational models.

Язык: Английский

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Formation of nuclear CPSF6/CPSF5 biomolecular condensates upon HIV-1 entry into the nucleus is important for productive infection

Scientific Reports, Год журнала: 2023, Номер 13(1)

Опубликована: Июль 6, 2023

The early events of HIV-1 infection involve the transport viral core into nucleus. This event triggers translocation CPSF6 from paraspeckles nuclear speckles forming puncta-like structures. Our investigations revealed that neither integration nor reverse transcription is required for formation Moreover, viruses without genome are competent induction In agreement with notion induced structures biomolecular condensates, we showed osmotic stress and 1,6-hexanediol disassembly condensates. Interestingly, replacing by isotonic media re-assemble condensates in cytoplasm cell. To test whether were important utilized hypertonic stress, which prevents during infection. Remarkably, preventing inhibits wild type but not bearing capsid changes N74D A77V, do form infection1,2. We also investigated functional partners recruited to upon experiments CPSF5, CPSF7, co-localized found containing CPSF6/CPSF5 human T cells primary macrophages Additionally, observed cofactor LEDGF/p75 distribution surrounds Overall, our work demonstrated CPSF5 viruses.

Язык: Английский

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