Asymmetric oligomerization state and sequence patterning can tune multiphase condensate miscibility

Nature Chemistry, Год журнала: 2024, Номер 16(7), С. 1073 - 1082

Опубликована: Фев. 21, 2024

Endogenous biomolecular condensates, composed of a multitude proteins and RNAs, can organize into multiphasic structures with compositionally distinct phases. This organization is generally understood to be critical for facilitating their proper biological function. However, the biophysical principles driving multiphase formation are not completely understood. Here we use in vivo condensate reconstitution experiments coarse-grained molecular simulations investigate how oligomerization sequence interactions modulate condensates. We demonstrate that increasing state an intrinsically disordered protein results enhanced immiscibility formation. Interestingly, find tunes miscibility asymmetric manner, effect being more pronounced when protein, exhibiting stronger homotypic interactions, oligomerized. Our findings suggest flexible mechanism cells exploit tune internal condensates associated functions.

Язык: Английский

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An RNA condensate model for the origin of life

Journal of Molecular Biology, Год журнала: 2025, Номер unknown, С. 169124 - 169124

Опубликована: Апрель 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.

Язык: Английский

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Asymmetric oligomerization state and sequence patterning can tune multiphase condensate miscibility

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Март 12, 2023

Abstract Endogenous biomolecular condensates, comprised of a multitude proteins and RNAs, can organize into multiphasic structures, with compositionally-distinct phases. This organization is generally understood to be critical for facilitating their proper biological function. However, the biophysical principles driving multiphase formation are not completely understood. Here, we utilize in vivo condensate reconstitution experiments coarse-grained molecular simulations investigate how oligomerization sequence interactions modulate condensates. We demonstrate that increasing state an intrinsically disordered protein region (IDR) results enhanced immiscibility formation. Interestingly, found tunes miscibility IDRs asymmetric manner, effect being more pronounced when IDR exhibiting stronger homotypic oligomerized. Our findings suggest flexible mechanism which cells exploit tune internal condensates associated functions.

Язык: Английский

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Role of the Psi Packaging Signal and Dimerization Initiation Sequence in the Organization of Rous Sarcoma Virus Gag-gRNA Co-Condensates

Viruses, Год журнала: 2025, Номер 17(1), С. 97 - 97

Опубликована: Янв. 13, 2025

Retroviral genome selection and virion assembly remain promising targets for novel therapeutic intervention. Recent studies have demonstrated that the Gag proteins of Rous sarcoma virus (RSV) human immunodeficiency type-1 (HIV-1) undergo nuclear trafficking, colocalize with nascent genomic viral RNA (gRNA) at transcription sites, may interact host factors, display biophysical properties characteristic biomolecular condensates. In present work, we utilized a controlled in vitro condensate assay advanced imaging approaches to investigate effects interactions between RSV condensates nonviral RNAs on abundance organization. We observed psi (Ψ) packaging signal dimerization initiation sequence (DIS) had stabilizing condensates, while lacking these features promoted or antagonized condensation, depending local protein concentration architecture. An containing Ψ, DIS, linkage structure (DLS) is capable stable dimer formation was act as bridge These observations suggest additional, condensate-related roles Gag-Ψ binding, gRNA dimerization, dimerization/multimerization packaging, representing significant step forward our understanding how collectively facilitate efficient packaging.

Язык: Английский

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Metal ion (Mⁿ⁺)‐condensed DNA nanoparticles: Synthesis, properties, and applications

Bulletin of the Korean Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Янв. 23, 2025

Abstract Metal ion (M n+ )‐induced DNA condensation is a critical process observed in both natural and synthetic contexts, playing central role the formation of nanoscale DNA‐based materials. This phenomenon leverages ability multivalent M s to neutralize negatively charged phosphate backbone, promote electrostatic cross‐linking, enable coordination bonding, leading compact organized nanostructures. Recent advancements have focused on synthesizing ‐condensed nanoparticles ‐CDNPs) through controlled molecular assembly, utilizing interplay sequence specificity, type, environmental conditions. The choice significantly influences properties ‐CDNPs, imparting functionalities including fluorescence, magnetism, catalytic activity, which are tailored for applications biosensing, diagnostics, therapeutic delivery. However, several challenges remain fully realizing potential ‐CDNPs. These include scalability issues, morphological control beyond isotropic spherical nanoparticles, ensuring biocompatibility, particularly when using heavy s. Innovations synthesis strategies, such as optimizing phase transitions during incorporating programmable sequences, enabled enhanced structural precision functionality. Surface modification techniques, coating with metal–organic frameworks (MOFs) or silica shells, further expanded stability applicability Additionally, inclusion functional additives, drugs proteins, has broadened their use targeted therapy release systems. review highlights advances synthesis, properties, emphasizing multifunctional platforms biomedical nanotechnological innovations. Future efforts must address reproducibility, toxicity, diversity interdisciplinary approaches combining experimental, computational, engineering strategies. By overcoming these barriers, ‐CDNPs hold promise transformative nanomedicine, chemical sensing, material design.

Язык: Английский

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Fluorescence Loss After Photoactivation (FLAPh): A Pulse-Chase Cellular Assay for Understanding Kinetics and Dynamics of Viral Inclusions

Methods in molecular biology, Год журнала: 2025, Номер unknown, С. 125 - 140

Опубликована: Янв. 1, 2025

Язык: Английский

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Nonviral protein cages as tools to decipher and combat viral threats

npj Viruses, Год журнала: 2025, Номер 3(1)

Опубликована: Май 26, 2025

Zoonotic viruses rank among the greatest threats to public health, with urbanization and global warming accelerating their emergence spread. As risk of future pandemics grows, innovative tools are needed deepen our understanding viral pathogenesis enhance pandemic preparedness. Nonviral protein cages provide a versatile platform for studying mechanisms, virus-host interactions, designing next-generation therapeutic approaches, making them powerful assets in fight against threats.

Язык: Английский

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Conserved molecular recognition by an intrinsically disordered region in the absence of sequence conservation

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Авг. 7, 2023

Intrinsically disordered regions (IDRs) are critical for cellular function, yet often appear to lack sequence conservation when assessed by multiple alignments. This raises the question of if and how function can be encoded preserved in these despite massive variation. To address this question, we have applied coarse-grained molecular dynamics simulations investigate non-specific RNA binding coronavirus nucleocapsid proteins. Coronavirus proteins consist interspersed folded domains that bind RNA. We focussed here on first two proteins, N-terminal domain (NTD) followed (RBD). While NTD is highly variable across evolution, RBD structurally conserved. combination makes NTD-RBD a convenient model system explore interplay between an IDR adjacent domain, changes influence recognition partner. Our results reveal surprising degree sequence-specificity both composition precise order amino acids NTD. The presence - depending either suppress or enhance binding. Despite sensitivity, large-scale variation sequences possible while certain features retained. Consequently, conformationally-conserved fuzzy RNA:protein complex found protein orthologs, surface chemistry. Taken together, insights shed light ability preserve functional characteristics their variability.

Язык: Английский

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Stepwise virus assembly in the cell nucleus revealed by spatiotemporal click chemistry of DNA replication

Science Advances, Год журнала: 2024, Номер 10(43)

Опубликована: Окт. 25, 2024

Biomolecular assemblies are fundamental to life and viral disease. The spatiotemporal coordination of replication assembly is largely unknown. Here, we developed a dual-color click chemistry procedure for imaging adenovirus DNA (vDNA) in the cell nucleus. Late- but not early-replicated vDNA was packaged into virions. Early-replicated segregated from compartment (VRC). Single object tracking, superresolution microscopy, fluorescence recovery after photobleaching, correlative light-electron microscopy revealed stepwise program involving capsid intermediates. Depending on scaffolding protein 52K, late-replicated with rapidly exchanging green fluorescent protein-tagged linchpin V incomplete virions emerged VRC periphery. These nanogel-like puncta exhibited restricted movements were located proteins hexon, VI, nuclear periphery, suggestive sites virion formation. Our findings identify dynamics intermediates, essential productive morphogenesis.

Язык: Английский

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Virus Induced Membraneless Organelles and Biomolecular Condensates

Journal of Molecular Biology, Год журнала: 2023, Номер 435(16), С. 168213 - 168213

Опубликована: Июль 20, 2023

Язык: Английский

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