Length-dependent Intramolecular Coil-to-Globule Transition in Poly(ADP-ribose) Induced by Cations DOI Open Access
Tong Wang, Kush Coshic, Mohsen Badiee

et al.

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

Published: Oct. 27, 2023

Poly(ADP-ribose) (PAR), as part of a post-translational modification, serves flexible scaffold for noncovalent protein binding. Such binding is influenced by PAR chain length through mechanism yet to be elucidated. Structural insights have been elusive, partly due the difficulties associated with synthesizing chains defined lengths. Here, we employ an integrated approach combining molecular dynamics (MD) simulations small-angle X-ray scattering (SAXS) experiments, enabling us identify highly heterogeneous ensembles conformers at two different, physiologically relevant lengths:

Language: Английский

Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD DOI Creative Commons
Bilal Khalil,

Miriam Linsenmeier,

Courtney L. Smith

et al.

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: Jan. 22, 2024

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that characterized by the cytoplasmic mislocalization aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), other nuclear RBPs detergent-insoluble aggregates cytoplasm degenerating neurons ALS/FTD is connected to pore dysfunction defects nucleocytoplasmic transport machinery. Recent advances suggest beyond their canonical role import protein cargoes, nuclear-import receptors (NIRs) can prevent reverse TDP-43, FUS, related restore localization function. Here, we showcase NIR family how they recognize cargo, drive import, chaperone linked ALS/FTD. We also discuss promise enhancing levels developing potentiated variants as therapeutic strategies for proteinopathies.

Language: Английский

Citations

14
Parthanatos: Mechanisms, modulation, and therapeutic prospects in neurodegenerative disease and stroke DOI
Yang Liu,

Lauren Guttman,

Valina L. Dawson

et al.

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 228, P. 116174 - 116174

Published: March 27, 2024

Language: Английский

Citations

12
Structural insights and milestones in TDP-43 research: A comprehensive review of its pathological and therapeutic advances DOI Creative Commons
Mei Dang, Longjiang Wu, Xiaoying Zhang

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 141677 - 141677

Published: March 1, 2025

Transactive response (TAR) DNA-binding protein 43 (TDP-43) is a critical RNA/DNA-binding involved in various cellular processes, including RNA splicing, transcription regulation, and stability. Mislocalization aggregation of TDP-43 the cytoplasm are key features pathogenesis several neurodegenerative diseases, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD). This review provides comprehensive retrospective prospective analysis research, highlighting structural insights, significant milestones, evolving understanding its physiological pathological functions. We delineate five major stages from initial discovery as hallmark neurodegeneration to recent advances liquid-liquid phase separation (LLPS) behavior interactions with processes. Furthermore, we assess therapeutic strategies targeting pathology, categorizing approaches into direct indirect interventions, alongside modulating aberrant LLPS. propose that future research will focus on three areas: polymorphisms for disease-specific therapeutics, exploring dual temporal-spatial modulation TDP-43, advancing nano-therapy. More importantly, emphasize importance TDP-43's functional repertoire at mesoscale, which bridges molecular functions broader offers foundational framework development.

Language: Английский

Citations

1
Liquid‒liquid phase separation and poly(ADP‒ribosyl)ation in the context of ultraviolet radiation-induced stress in mammalian cells DOI

Daniela Mejías,

Valentina Seballos, Laura Lafon-Hughes

et al.

Biophysical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: March 11, 2025

Language: Английский

Citations

1
PARP enzyme de novo synthesis of protein-free poly(ADP-ribose) DOI
Marie-France Langelier,

Manija Mirhasan,

Karine Gilbert

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Language: Английский

Citations

5
Cation-induced intramolecular coil-to-globule transition in poly(ADP-ribose) DOI Creative Commons
Tong Wang, Kush Coshic, Mohsen Badiee

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Sept. 10, 2024

Language: Английский

Citations

4
Regulation of stress granule maturation and dynamics by poly(ADP-ribose) interaction with PARP13 DOI Creative Commons
Shang-Jung Cheng,

Temitope Gafaar,

Jijin R. A. Kuttiyatveetil

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 13, 2025

Non-covalent interactions of poly(ADP-ribose) (PAR) facilitate condensate formation, yet the impact these on properties remains unclear. Here, we demonstrate that PAR-mediated through PARP13, specifically PARP13.2 isoform, are essential for modulating dynamics stress granules—a class cytoplasmic condensates form upon stress, including types frequently observed in cancers. Single amino acid mutations which reduce its PAR-binding activity, lead to formation smaller more numerous granules than wild-type. This fragmented granule phenotype is also apparent PARP13 variants with cancer-associated single-nucleotide polymorphisms (SNPs) disrupt PAR binding. Notably, this conserved across a variety stresses trigger via diverse pathways. Furthermore, mutant diminishes and impedes fusion. Overall, our study uncovers important role PAR-protein maturation, mediated PARP13. Stress granules, cellular structures response, require as multivalent scaffold. authors show disrupting binding alters size, dynamics, despite lacking ADPribosyltransferase activity.

Language: Английский

Citations

0
Divalent and multivalent cations control liquid-like assembly of poly(ADP-ribosyl)ated PARP1 into multimolecular associates in vitro DOI Creative Commons
Maria V. Sukhanova,

Rashid O. Anarbaev,

Ekaterina A. Maltseva

et al.

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: Sept. 15, 2024

Language: Английский

Citations

3
Phase Separation of FUS with Poly(ADP-ribosyl)ated PARP1 Is Controlled by Polyamines, Divalent Metal Cations, and Poly(ADP-ribose) Structure DOI Open Access
Maria V. Sukhanova,

Rashid O. Anarbaev,

Konstantin N. Naumenko

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(22), P. 12445 - 12445

Published: Nov. 20, 2024

Fused in sarcoma (FUS) is involved the formation of nuclear biomolecular condensates associated with poly(ADP-ribose) [PAR] synthesis catalyzed by a DNA damage sensor such as PARP1. Here, we studied FUS microphase separation induced poly(ADP-ribosyl)ated PARP1

Language: Английский

Citations

3
Phase separation in DNA repair: orchestrating the cellular response to genomic stability DOI Creative Commons
Jinghao Deng, Zhiping Du, Lei Li

et al.

PeerJ, Journal Year: 2025, Volume and Issue: 13, P. e19402 - e19402

Published: May 2, 2025

DNA repair is a hierarchically organized, spatially and temporally regulated process involving numerous factors that respond to various types of damage. Despite decades research, the mechanisms by which these are recruited depart from sites have been subject intrigue. Recent advancements in field increasingly highlighted role phase separation as critical facilitator efficiency repair. This review emphasizes how enhances concentration coordination at damage sites, optimizing efficiency. Understanding dysregulation can impair alter nuclear organization, potentially leading diseases such cancer neurodegenerative disorders, crucial. manuscript provides comprehensive understanding pivotal repair, sheds light on current suggests potential future directions for research therapeutic interventions.

Language: Английский

Citations

0