Interplay between charge distribution and DNA in shaping HP1 paralog phase separation and localization DOI Creative Commons
Tien M. Phan,

Young C. Kim,

Galia T. Debelouchina

et al.

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Oct. 5, 2023

The heterochromatin protein 1 (HP1) family is a crucial component of with diverse functions in gene regulation, cell cycle control, and differentiation. In humans, there are three paralogs, HP1α, HP1β, HP1γ, which exhibit remarkable similarities their domain architecture sequence properties. Nevertheless, these paralogs display distinct behaviors liquid-liquid phase separation (LLPS), process linked to formation. Here, we employ coarse-grained simulation framework uncover the features responsible for observed differences LLPS. We highlight significance net charge patterning along governing paralog LLPS propensities. also show that both highly conserved folded less-conserved disordered domains contribute differences. Furthermore, explore potential co-localization different HP1 multicomponent assemblies impact DNA on this process. Importantly, our study reveals can significantly reshape stability minimal condensate formed by due competitive interactions HP1α HP1β HP1γ versus DNA. conclusion, work highlights physicochemical nature govern phase-separation provides molecular understanding role chromatin organization.

Language: Английский

Coiled-coil domains are sufficient to drive liquid-liquid phase separation in protein models DOI
Dominique Ramirez, Loren E. Hough, Michael R. Shirts

et al.

Biophysical Journal, Journal Year: 2024, Volume and Issue: 123(6), P. 703 - 717

Published: Feb. 15, 2024

Language: Английский

Citations

16
Phase separation as a new form of regulation in innate immunity DOI
Lei Wang, Wen Zhou

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(13), P. 2410 - 2422

Published: June 26, 2024

Language: Английский

Citations

11
Interplay between charge distribution and DNA in shaping HP1 paralog phase separation and localization DOI Creative Commons
Tien M. Phan,

Young C. Kim,

Galia T. Debelouchina

et al.

eLife, Journal Year: 2024, Volume and Issue: 12

Published: April 9, 2024

The heterochromatin protein 1 (HP1) family is a crucial component of with diverse functions in gene regulation, cell cycle control, and differentiation. In humans, there are three paralogs, HP1α, HP1β, HP1γ, which exhibit remarkable similarities their domain architecture sequence properties. Nevertheless, these paralogs display distinct behaviors liquid-liquid phase separation (LLPS), process linked to formation. Here, we employ coarse-grained simulation framework uncover the features responsible for observed differences LLPS. We highlight significance net charge patterning along governing paralog LLPS propensities. also show that both highly conserved folded less-conserved disordered domains contribute differences. Furthermore, explore potential co-localization different HP1 multicomponent assemblies impact DNA on this process. Importantly, our study reveals can significantly reshape stability minimal condensate formed by due competitive interactions HP1α HP1β HP1γ versus DNA. conclusion, work highlights physicochemical nature govern phase-separation provides molecular understanding role chromatin organization.

Language: Английский

Citations

10
Emerging regulatory mechanisms and functions of biomolecular condensates: implications for therapeutic targets DOI Creative Commons
Soyoung Jeon, Yong‐Duck Chung, Jae‐Sung Lim

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 6, 2025

Cells orchestrate their processes through complex interactions, precisely organizing biomolecules in space and time. Recent discoveries have highlighted the crucial role of biomolecular condensates-membrane-less assemblies formed condensation proteins, nucleic acids, other molecules-in driving efficient dynamic cellular processes. These condensates are integral to various physiological functions, such as gene expression intracellular signal transduction, enabling rapid finely tuned responses. Their ability regulate signaling pathways is particularly significant, it requires a careful balance between flexibility precision. Disruption this can lead pathological conditions, including neurodegenerative diseases, cancer, viral infections. Consequently, emerged promising therapeutic targets, with potential offer novel approaches disease treatment. In review, we present recent insights into regulatory mechanisms by which influence pathways, roles health disease, strategies for modulating condensate dynamics approach. Understanding these emerging principles may provide valuable directions developing effective treatments targeting aberrant behavior diseases.

Language: Английский

Citations

1
Molecular interactions underlying the phase separation of HP1α: role of phosphorylation, ligand and nucleic acid binding DOI Creative Commons

Cheenou Her,

Tien M. Phan,

Nina Jovic

et al.

Nucleic Acids Research, Journal Year: 2022, Volume and Issue: 50(22), P. 12702 - 12722

Published: Dec. 9, 2022

Abstract Heterochromatin protein 1α (HP1α) is a crucial element of chromatin organization. It has been proposed that HP1α functions through liquid-liquid phase separation (LLPS), which allows it to compact into transcriptionally repressed heterochromatin regions. In vitro, can undergo upon phosphorylation its N-terminus extension (NTE) and/or interactions with DNA and chromatin. Here, we combine computational experimental approaches elucidate the molecular drive these processes. phosphorylation-driven LLPS, exchange intradimer hinge-NTE interdimer contacts, also leads structural change from compacted an extended dimer conformation. This process be enhanced by presence positively charged peptide ligands disrupted addition negatively or neutral peptides. DNA-driven both perturb separation. Our findings demonstrate importance electrostatic in LLPS where binding partners modulate overall charge droplets screen enhance hinge region specific non-specific effects. study illuminates complex framework fine-tune properties contribute regulation function.

Language: Английский

Citations

38
A Zn‐dependent structural transition of SOD1 modulates its ability to undergo phase separation DOI Open Access
Bidisha Das, Sumangal Roychowdhury, Priyesh Mohanty

et al.

The EMBO Journal, Journal Year: 2022, Volume and Issue: 42(2)

Published: Nov. 23, 2022

Language: Английский

Citations

36
Effect of Charge Distribution on the Dynamics of Polyampholytic Disordered Proteins DOI
Dinesh Sundaravadivelu Devarajan, Shiv Rekhi, Arash Nikoubashman

et al.

Macromolecules, Journal Year: 2022, Volume and Issue: 55(20), P. 8987 - 8997

Published: Oct. 12, 2022

The stability and physiological function of many biomolecular coacervates depend on the structure dynamics intrinsically disordered proteins (IDPs) that typically contain a significant fraction charged residues. Although effect relative arrangement residues IDP conformation is well-studied problem, associated changes in are far less understood. In this work, we systematically interrogate effects charge distribution chain-level segmental polyampholytic IDPs dilute solutions. We study coarse-grained model polyampholyte consisting an equal two oppositely (glutamic acid lysine) undergoes transition from ideal chain-like for uniformly charge-patterned sequences to semi-compact highly charge-segregated sequences. Changes with increasing segregation correlate conformation. conform simple homopolymer models but deviate segregation, both presence absence hydrodynamic interactions. discuss significance these findings, obtained polyampholyte, context charge-rich region naturally occurring protein LAF-1. Our findings have important implications understanding patterning conditions using polymer scaling theories.

Language: Английский

Citations

30
A complex network of interdomain interactions underlies the conformational ensemble of monomeric TDP‐43 and modulates its phase behavior DOI Creative Commons
Priyesh Mohanty, Azamat Rizuan,

Young C. Kim

et al.

Protein Science, Journal Year: 2023, Volume and Issue: 33(2)

Published: Dec. 31, 2023

TAR DNA-binding protein 43 (TDP-43) is a multidomain involved in the regulation of RNA metabolism, and its aggregates have been observed neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) frontotemporal dementia (FTD). Numerous studies indicate TDP-43 can undergo liquid-liquid phase separation (LLPS) vitro component biological condensates. Homo-oligomerization via folded N-terminal domain (aa:1-77) conserved helical region (aa:319-341) disordered, C-terminal found to be an important driver separation. However, comprehensive molecular view separation, particularly regarding nature heterodomain interactions, lacking due challenges associated with stability purification. Here, we utilize all-atom coarse-grained (CG) dynamics (MD) simulations uncover network interdomain interactions implicated All-atom uncovered presence transient, involving flexible linkers, RNA-recognition motif (RRM) domains charged segment disordered (CTD). CG these inter-domain which affect conformational landscape dilute are also prevalent condensed phase. Finally, sequence surface charge distribution analysis coupled (at high salt) confirmed that transient contacts predominantly electrostatic nature. Overall, our findings from multiscale lead greater appreciation complex interaction underlying structural TDP-43.

Language: Английский

Citations

20
Challenges in studying the liquid-to-solid phase transitions of proteins using computer simulations DOI Creative Commons
Beata Szała-Mendyk, Tien M. Phan, Priyesh Mohanty

et al.

Current Opinion in Chemical Biology, Journal Year: 2023, Volume and Issue: 75, P. 102333 - 102333

Published: May 31, 2023

Language: Английский

Citations

17
Programmable de novo designed coiled coil-mediated phase separation in mammalian cells DOI Creative Commons

Maruša Ramšak,

Dominique Ramirez, Loren E. Hough

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Dec. 2, 2023

Abstract Membraneless liquid compartments based on phase-separating biopolymers have been observed in diverse cell types and attributed to weak multivalent interactions predominantly intrinsically disordered domains. The design of liquid-liquid phase separated (LLPS) condensates de novo designed tunable modules that interact a well-understood, controllable manner could improve our understanding this phenomenon enable the introduction new features. Here we report construction CC-LLPS mammalian cells, coiled-coil (CC) dimer-forming modules, where stability CC pairs, their number, linkers, sequential arrangement govern transition between diffuse, immobile are corroborated by coarse-grained molecular simulations. Through modular design, achieve multiple coexisting condensates, chemical regulation LLPS, condensate fusion, formation from either one or two polypeptide components LLPS third chain. These findings provide further insights into principles underlying platform for controlling biological processes.

Language: Английский

Citations

17