Treacle’s ability to form liquid-like phase condensates is essential for nucleolar fibrillar center assembly, efficient rRNA transcription and processing, and rRNA gene repair DOI Creative Commons

Artem K. Velichko,

Nadezhda V. Petrova,

Dmitry A Deriglazov

et al.

eLife, Journal Year: 2025, Volume and Issue: 13

Published: April 14, 2025

We investigated the role of nucleolar protein Treacle in organizing and regulating nucleolus human cells. Our results support Treacle’s ability to form liquid-like phase condensates through electrostatic interactions among molecules. The formation these biomolecular is crucial for segregating fibrillar centers from dense component ensuring high levels ribosomal RNA (rRNA) gene transcription accurate rRNA processing. Both central C-terminal domains are required condensates. initiation separation attributed domain. domain characterized by repeated stretches alternatively charged amino acid residues vital condensate stability. Overexpression mutant forms that cannot compromises assembly centers, suppressing disrupting These also fail recruit DNA topoisomerase II binding 1 (TOPBP1), damage response nucleolus.

Language: Английский

The molecular basis for cellular function of intrinsically disordered protein regions DOI
Alex S. Holehouse, Birthe B. Kragelund

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 25(3), P. 187 - 211

Published: Nov. 13, 2023

Language: Английский

Citations

235
Functional partitioning of transcriptional regulators by patterned charge blocks DOI Creative Commons
Heankel Lyons,

Reshma T Veettil,

Prashant Pradhan

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(2), P. 327 - 345.e28

Published: Jan. 1, 2023

Language: Английский

Citations

189
Conformational ensembles of the human intrinsically disordered proteome DOI
Giulio Tesei, Anna Ida Trolle, Nicolas Jonsson

et al.

Nature, Journal Year: 2024, Volume and Issue: 626(8000), P. 897 - 904

Published: Jan. 31, 2024

Language: Английский

Citations

133
A brief guideline for studies of phase-separated biomolecular condensates DOI

Yifei Gao,

Xi Li,

Pilong Li

et al.

Nature Chemical Biology, Journal Year: 2022, Volume and Issue: 18(12), P. 1307 - 1318

Published: Nov. 18, 2022

Language: Английский

Citations

101
Molecular determinants of condensate composition DOI Creative Commons
Alex S. Holehouse, Simon Alberti

Molecular Cell, Journal Year: 2025, Volume and Issue: 85(2), P. 290 - 308

Published: Jan. 1, 2025

Language: Английский

Citations

4
Chemically Informed Coarse-Graining of Electrostatic Forces in Charge-Rich Biomolecular Condensates DOI Creative Commons
Andrés R. Tejedor,

Anne Aguirre Gonzalez,

Maria Julia Maristany

et al.

ACS Central Science, Journal Year: 2025, Volume and Issue: 11(2), P. 302 - 321

Published: Feb. 11, 2025

Biomolecular condensates composed of highly charged biomolecules, such as DNA, RNA, chromatin, and nucleic-acid binding proteins, are ubiquitous in the cell nucleus. The biophysical properties these charge-rich largely regulated by electrostatic interactions. Residue-resolution coarse-grained models that describe solvent ions implicitly widely used to gain mechanistic insights into condensates, offering transferability, computational efficiency, accurate predictions for multiple systems. However, their predictive accuracy diminishes due implicit treatment ions. Here, we present Mpipi-Recharged, a residue-resolution model improves description charge effects biomolecular containing disordered multidomain and/or single-stranded RNAs. Mpipi-Recharged introduces pair-specific asymmetric Yukawa potential, informed atomistic simulations. We show this coarse-graining forces captures intricate effects, blockiness, stoichiometry variations complex coacervates, modulation salt concentration, without requiring explicit solvation. provides excellent agreement with experiments predicting phase behavior condensates. Overall, tools available investigate physicochemical mechanisms regulating enhancing scope computer simulations field.

Language: Английский

Citations

2
SRRM2 phase separation drives assembly of nuclear speckle subcompartments DOI Creative Commons
Mengjun Zhang, Zhuang Gu,

Shuanghui Guo

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(3), P. 113827 - 113827

Published: Feb. 20, 2024

Nuclear speckles (NSs) are nuclear biomolecular condensates that postulated to form by macromolecular phase separation, although the detailed underlying forces driving NS formation remain elusive. SRRM2 and SON 2 non-redundant scaffold proteins for NSs. How each individual protein governs assembly of network functional relationship between largely unknown. Here, we uncover immiscible multiphases within functionally independent, specifically regulating alternative splicing subsets mRNA targets, respectively. We further show forms multicomponent liquid phases in cells drive subcompartmentalization, which is reliant on homotypic interaction heterotypic non-selective protein-RNA complex coacervation-driven separation. serine/arginine-rich (RS) domains higher-order oligomers can be replaced oligomerizable synthetic modules. The serine residues RS domains, however, play an irreplaceable role fine-tuning liquidity

Language: Английский

Citations

16
Conformational ensembles of the human intrinsically disordered proteome: Bridging chain compaction with function and sequence conservation DOI Creative Commons
Giulio Tesei, Anna Ida Trolle, Nicolas Jonsson

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: May 8, 2023

Abstract Intrinsically disordered proteins and regions (collectively IDRs) are pervasive across proteomes in all kingdoms of life, help shape biological functions, involved numerous diseases. IDRs populate a diverse set transiently formed structures, yet defy commonly held sequence-structure-function relationships. Recent developments protein structure prediction have led to the ability predict three-dimensional structures folded at proteome scale, enabled large-scale studies structure-function In contrast, knowledge conformational properties is scarce, part because sequences poorly conserved only few been characterized experimentally. We developed an efficient model generate ensembles IDRs, thereby their from sequence only. Here, we applied this simulate human proteome. Examining 29,998 show how chain compaction correlated with cellular function localization, including different types biomolecular condensates. train use conservation structural orthologs. Our results recapitulate observations previous individual systems, enable us study relationship between sequence, conservation, ensembles, disease variants scale.

Language: Английский

Citations

22
The regulatory landscape of the yeast phosphoproteome DOI
Mario Leutert, Anthony S. Barente, Noelle K. Fukuda

et al.

Nature Structural & Molecular Biology, Journal Year: 2023, Volume and Issue: 30(11), P. 1761 - 1773

Published: Oct. 16, 2023

Language: Английский

Citations

21
An ERK1/2‐driven RNA‐binding switch in nucleolin drives ribosome biogenesis and pancreatic tumorigenesis downstream of RAS oncogene DOI Creative Commons

Muhammad S. Azman,

Emilie Louise Alard, Martin Dodel

et al.

The EMBO Journal, Journal Year: 2023, Volume and Issue: 42(11)

Published: April 11, 2023

Abstract Oncogenic RAS signaling reprograms gene expression through both transcriptional and post‐transcriptional mechanisms. While regulation downstream of is relatively well characterized, how post‐transcriptionally modulates to promote malignancy remains largely unclear. Using quantitative RNA interactome capture analysis, we here reveal that oncogenic reshapes the RNA‐bound proteomic landscape pancreatic cancer cells, with a network nuclear proteins centered around nucleolin displaying enhanced RNA‐binding activity. We show phosphorylated RAS, which increases its binding pre‐ribosomal (rRNA), boosts rRNA production, promotes ribosome biogenesis. This nucleolin‐dependent enhancement biogenesis crucial for RAS‐induced cell proliferation can be targeted therapeutically inhibit tumor growth. Our results drives by regulating activity highlight role this mechanism in RAS‐mediated tumorigenesis.

Language: Английский

Citations

20