Nuclear transport proteins: structure, function, and disease relevance

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Ноя. 10, 2023

Abstract Proper subcellular localization is crucial for the functioning of biomacromolecules, including proteins and RNAs. Nuclear transport a fundamental cellular process that regulates many macromolecules within nuclear or cytoplasmic compartments. In humans, approximately 60 are involved in transport, nucleoporins form membrane-embedded pore complexes, karyopherins cargoes through these Ran system ensure directed rapid transport. Many play additional essential roles mitosis, biomolecular condensation, gene transcription. Dysregulation linked to major human diseases such as cancer, neurodegenerative diseases, viral infections. Selinexor (KPT-330), an inhibitor targeting export factor XPO1 (also known CRM1), was approved 2019 treat two types blood cancers, dozens clinical trials ongoing. This review summarizes three decades research data this field but focuses on structure function individual from recent studies, providing cutting-edge holistic view role health disease. In-depth knowledge rapidly evolving has potential bring new insights into biology, pathogenic mechanisms, therapeutic approaches.

Язык: Английский

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The nexus between RNA-binding proteins and their effectors

Nature Reviews Genetics, Год журнала: 2022, Номер 24(5), С. 276 - 294

Опубликована: Ноя. 23, 2022

Язык: Английский

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Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD

Molecular Neurodegeneration, Год журнала: 2024, Номер 19(1)

Опубликована: Янв. 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.

Язык: Английский

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Structural basis for nuclear import of hepatitis B virus (HBV) nucleocapsid core

Science Advances, Год журнала: 2024, Номер 10(2)

Опубликована: Янв. 10, 2024

Nuclear import of the hepatitis B virus (HBV) nucleocapsid is essential for replication that occurs in nucleus. The ~360-angstrom HBV capsid translocates to nuclear pore complex (NPC) as an intact particle, hijacking human importins a reaction stimulated by host kinases. This paper describes mechanisms recognition importins. We found importin α1 binds localization signal (NLS) at far end coat protein Cp183 carboxyl-terminal domain (CTD). NLS exposed surface through icosahedral quasi-sixfold vertex. Phosphorylation serine-155, serine-162, and serine-170 promotes CTD compaction but does not affect affinity α1. binding 30 α1/β1 augments diameter ~620 angstroms, close maximum size trafficable NPC. propose phosphorylation favors externalization prompts its surface, exposing

Язык: Английский

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A quantitative and site-specific atlas of the citrullinome reveals widespread existence of citrullination and insights into PADI4 substrates

Nature Structural & Molecular Biology, Год журнала: 2024, Номер 31(6), С. 977 - 995

Опубликована: Фев. 6, 2024

Abstract Despite the importance of citrullination in physiology and disease, global identification citrullinated proteins, precise targeted sites, has remained challenging. Here we employed quantitative-mass-spectrometry-based proteomics to generate a comprehensive atlas sites within HL60 leukemia cell line following differentiation into neutrophil-like cells. We identified 14,056 4,008 proteins quantified their regulation upon inhibition citrullinating enzyme PADI4. With this resource, provide quantitative site-specific information on thousands PADI4 substrates, including signature histone marks transcriptional regulators. Additionally, using peptide microarrays, demonstrate potential clinical relevance certain through distinct reactivities antibodies contained synovial fluid from anti-CCP-positive anti-CCP-negative people with rheumatoid arthritis. Collectively, describe human citrullinome at systems-wide level, resource for understanding mechanistic level link

Язык: Английский

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Structural insights and milestones in TDP-43 research: A comprehensive review of its pathological and therapeutic advances

International Journal of Biological Macromolecules, Год журнала: 2025, Номер unknown, С. 141677 - 141677

Опубликована: Март 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.

Язык: Английский

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Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence

Acta Neuropathologica Communications, Год журнала: 2025, Номер 13(1)

Опубликована: Март 8, 2025

Abstract TDP-43 mislocalization and aggregation are key pathological features of amyotrophic lateral sclerosis (ALS)- frontotemporal dementia (FTD). However, existing transgenic hTDP-43 WT or ∆NLS-overexpression animal models primarily focus on late-stage proteinopathy. To complement these to study the early-stage motor neuron-specific pathology during pre-symptomatic phases disease progression, we generated a new endogenous knock-in (KI) mouse model using combination CRISPR/Cas9 FLEX Cre-switch strategy for conditional expression mislocalized Tdp-43∆NLS variant Tdp-43. This is expressed either in whole body (WB) specifically neurons (MNs) two distinct models. These mice exhibit loss nuclear Tdp-43, with concomitant cytosolic accumulation targeted cells, leading increased DNA double-strand breaks (DSBs), signs inflammation, associated cellular senescence. Notably, unlike which functionally interacts Xrcc4 Ligase 4, DSB repair proteins non-homologous end-joining (NHEJ) pathway, mutant sequesters them into aggregates, exacerbating neuronal damage brain. The also myogenic degeneration hindlimb soleus muscles deficits, consistent characteristics neuron (MND). Our findings reveal progressive degenerative mechanisms expressing mutant, independent Tdp-43 overexpression other confounding factors. Thus, this unique KI model, displays molecular phenotypic proteinopathy, offers significant opportunity characterize progression MND further opens avenues developing repair-targeted approaches treating pathology-linked neurodegenerative diseases.

Язык: Английский

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Nuclear import receptors are recruited by FG-nucleoporins to rescue hallmarks of TDP-43 proteinopathy

Molecular Neurodegeneration, Год журнала: 2022, Номер 17(1)

Опубликована: Дек. 8, 2022

Abstract Background Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark the amyotrophic lateral sclerosis frontotemporal dementia (ALS/FTD) disease spectrum, causing both nuclear loss-of-function cytoplasmic toxic gain-of-function phenotypes. While TDP-43 proteinopathy has been associated with defects in nucleocytoplasmic transport, this process still poorly understood. Here we study role karyopherin-β1 (KPNB1) other import receptors regulating pathology. Methods We used immunostaining, immunoprecipitation, biochemical toxicity assays cell lines, primary neuron organotypic mouse brain slice cultures, to determine impact KPNB1 on solubility, localization, pathological constructs. Postmortem patient spinal cord tissue was stained assess colocalization inclusions. Turbidity were employed dissolution prevention recombinant fibrils vitro. Fly models effect their neurodegenerative phenotype vivo. Results discovered that several members receptor protein family can reduce formation aggregates. Using as model, found its activity depends prion-like C-terminal region TDP-43, which mediates co-aggregation phenylalanine glycine-rich nucleoporins (FG-Nups) such Nup62. recruited into these co-aggregates where it acts molecular chaperone reverses aberrant phase transition Nup62 TDP-43. These findings are supported by discovery also sequestered aggregates ALS/FTD postmortem CNS tissue, identification fly ortholog strong protective modifier Drosophila proteinopathy. Our results show rescue all hallmarks pathology, restoring solubility reducing neurodegeneration cellular animal ALS/FTD. Conclusion suggest novel NLS-independent mechanism where, analogous canonical dissolving diffusion barrier formed FG-Nups pore, TDP-43/FG-Nup present proteinopathies therapeutically deleterious mislocalization, mitigating neurodegeneration. Graphical

Язык: Английский

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A complex network of interdomain interactions underlies the conformational ensemble of monomeric TDP‐43 and modulates its phase behavior

Protein Science, Год журнала: 2023, Номер 33(2)

Опубликована: Дек. 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.

Язык: Английский

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Regulation of Biomolecular Condensates by Poly(ADP-ribose)

Chemical Reviews, Год журнала: 2023, Номер 123(14), С. 9065 - 9093

Опубликована: Апрель 28, 2023

Biomolecular condensates are reversible compartments that form through a process called phase separation. Post-translational modifications like ADP-ribosylation can nucleate the formation of these by accelerating self-association proteins. Poly(ADP-ribose) (PAR) chains remarkably transient with turnover rates on order minutes, yet they be required for granules in response to oxidative stress, DNA damage, and other stimuli. Moreover, accumulation PAR is linked adverse transitions neurodegenerative diseases, including Alzheimer's disease, Parkinson's amyotrophic lateral sclerosis. In this review, we provide primer how synthesized regulated, diverse structures chemistries modifications, protein–PAR interactions. We review substantial progress recent efforts determine molecular mechanism PAR-mediated separation, further delineate inhibitors polymerases may effective treatments pathologies. Finally, highlight need rigorous biochemical interrogation vivo vitro clarify exact pathway from PARylation condensate formation.

Язык: Английский

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