Cytoplasmic nucleoporin assemblage: the cellular artwork in physiology and disease DOI Creative Commons
Junyan Lin, Izabela Sumara

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

Published: Aug. 12, 2024

Nucleoporins, essential proteins building the nuclear pore, are pivotal for ensuring nucleocytoplasmic transport. While traditionally confined to envelope, emerging evidence indicates their presence in various cytoplasmic structures, suggesting potential non-transport-related roles. This review consolidates findings on nucleoporin assemblies across different states, including normal physiological conditions, stress, and pathology, exploring structural organization, formation dynamics, functional implications. We summarize current knowledge latest concepts regulation of homeostasis, aiming enhance our understanding unexpected roles pathological processes.

Language: Английский

Phase separation of intrinsically disordered FG-Nups is driven by highly dynamic FG motifs DOI Creative Commons
Maurice Dekker, E. van der Giessen, Patrick R. Onck

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(25)

Published: June 12, 2023

The intrinsically disordered FG-Nups in the central channel of nuclear pore complex (NPC) form a selective permeability barrier, allowing small molecules to traverse by passive diffusion, while large can only translocate with help transport receptors. exact phase state barrier remains elusive. In vitro experiments have shown that some undergo separation into condensates display NPC-like properties. Here, we use molecular dynamics simulations at amino acid resolution study characteristics each yeast NPC. We find GLFG-Nups and reveal FG motifs act as highly dynamic hydrophobic stickers are essential for formation FG-Nup featuring droplet-spanning percolated networks. Additionally, an mixture resembles NPC stoichiometry observe condensate is formed containing multiple GLFG-Nups. this also driven FG-FG interactions, similar homotypic condensates. Based on observed behavior, different be divided two classes: (mostly GLFG-type) located network many short-lived peripheral FxFG-type) entry exit likely entropic brush.

Language: Английский

Citations

32
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

16
Nuclear pore dysfunction and disease: a complex opportunity DOI Creative Commons
Charlotte M. Fare, Jeffrey D. Rothstein

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

Published: Feb. 21, 2024

The separation of genetic material from bulk cytoplasm has enabled the evolution increasingly complex organisms, allowing for development sophisticated forms life. However, this complexity created new categories dysfunction, including those related to movement between cellular compartments. In eukaryotic cells, nucleocytoplasmic trafficking is a fundamental biological process, and cumulative disruptions nuclear integrity transport are detrimental cell survival. This particularly true in post-mitotic neurons, where pore injury errors strongly associated with neurodegenerative disease. review, we summarize current understanding biology physiological pathological contexts discuss potential therapeutic approaches addressing dysfunctional transport.

Language: Английский

Citations

11
Atypical nuclear envelope condensates linked to neurological disorders reveal nucleoporin-directed chaperone activities DOI
Sarah Prophet, Anthony J. Rampello, Robert F. Niescier

et al.

Nature Cell Biology, Journal Year: 2022, Volume and Issue: 24(11), P. 1630 - 1641

Published: Oct. 27, 2022

Language: Английский

Citations

36
Improving the hole picture: towards a consensus on the mechanism of nuclear transport DOI Creative Commons
David Cowburn, Michael P. Rout

Biochemical Society Transactions, Journal Year: 2023, Volume and Issue: 51(2), P. 871 - 886

Published: April 26, 2023

Nuclear pore complexes (NPCs) mediate the exchange of materials between nucleoplasm and cytoplasm, playing a key role in separation nucleic acids proteins into their required compartments. The static structure NPC is relatively well defined by recent cryo EM other studies. functional roles dynamic components NPC, phenylalanyl-glycyl (FG) repeat rich nucleoporins, less clear because our limited understanding highly protein systems. These form restrained concentrate which interacts with concentrates nuclear transport factors (NTRs) to provide facilitated nucleocytoplasmic cargoes. Very rapid among FG repeats NTRs supports extremely fast transport, close rate macromolecular diffusion while without specific interactions are entropically excluded, though details on several aspects mechanism behaviors remain be resolved. However, as discussed here, new technical approaches combined more advanced modeling methods will likely an improved description potentially at atomic level near future. Such advances major benefit comprehending malfunctioning plays cancer, aging, viral diseases, neurodegeneration.

Language: Английский

Citations

22
DNAJB6 mutants display toxic gain of function through unregulated interaction with Hsp70 chaperones DOI Creative Commons

Meital Abayev-Avraham,

Yehuda Salzberg,

Dar Gliksberg

et al.

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

Published: Nov. 3, 2023

Molecular chaperones are essential cellular components that aid in protein folding and preventing the abnormal aggregation of disease-associated proteins. Mutations one such chaperone, DNAJB6, were identified patients with LGMDD1, a dominant autosomal disorder characterized by myofibrillar degeneration accumulations aggregated within myocytes. The molecular mechanisms through which mutations cause this dysfunction, however, not well understood. Here we employ combination solution NMR biochemical assays to investigate structural functional changes LGMDD1 mutants DNAJB6. Surprisingly, find DNAJB6 disease show no reduction their aggregation-prevention activity vitro, instead differ structurally from WT protein, affecting interaction Hsp70 chaperones. While contains helical element regulating its ability bind activate Hsp70, regulation is disrupted. These variants can thus recruit hyperactivate an unregulated manner, depleting levels myocytes, resulting disruption proteostasis. Interfering DNAJB6-Hsp70 binding, reverses phenotype, suggesting future therapeutic avenues for LGMDD1.

Language: Английский

Citations

19
J-domain proteins: From molecular mechanisms to diseases DOI Creative Commons
Jarosław Marszałek, Paolo De Los Rios, Douglas Cyr

et al.

Cell Stress and Chaperones, Journal Year: 2024, Volume and Issue: 29(1), P. 21 - 33

Published: Feb. 1, 2024

J-domain proteins (JDPs) are the largest family of chaperones in most organisms, but much how they function within network other and protein quality control machineries is still an enigma. Here, we report on latest findings related to JDP functions presented at a dedicated workshop Gdansk, Poland. The does not include all (details) what was shared discussed meeting, because some these original data have yet been accepted for publication elsewhere or represented preliminary observations time.

Language: Английский

Citations

9
Proxiome assembly of the plant nuclear pore reveals an essential hub for gene expression regulation DOI
Yu Tang,

Xiangyun Yang,

Aobo Huang

et al.

Nature Plants, Journal Year: 2024, Volume and Issue: 10(6), P. 1005 - 1017

Published: May 21, 2024

Language: Английский

Citations

9
Dynamic molecular mechanism of the nuclear pore complex permeability barrier DOI Creative Commons
Toshiya Kozai, Javier Fernández-Martı́nez, Trevor van Eeuwen

et al.

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

Published: April 3, 2023

Abstract Nuclear pore complexes (NPCs) mediate nucleocytoplasmic transport of specific macromolecules while impeding the exchange unsolicited material. However, key aspects this gating mechanism remain controversial. To address issue, we determined nanoscopic behavior permeability barrier directly within yeast S. cerevisiae NPCs at transport-relevant timescales. We show that large intrinsically disordered domains phenylalanine-glycine repeat nucleoporins (FG Nups) exhibit highly dynamic fluctuations to create transient voids in continuously shape-shift and reseal, resembling a radial polymer brush. Together with cargo-carrying factors FG form feature called central plug, which is also dynamic. Remarkably, NPC mutants longer interweaving meshwork-like attenuates vivo . Importantly, bona fide nanoscale behaviors morphologies are not recapitulated by vitro domain hydrogels. exclude self-assembling condensates , thereby indicating generated phase condensate, but rather largely brush, organized scaffold, whose selectivity strongly enhanced presence factors.

Language: Английский

Citations

17
DNAJB8 oligomerization is mediated by an aromatic-rich motif that is dispensable for substrate activity DOI Creative Commons
Bryan D. Ryder, Elizaveta Ustyantseva, David R. Boyer

et al.

Structure, Journal Year: 2024, Volume and Issue: 32(6), P. 662 - 678.e8

Published: March 19, 2024

Language: Английский

Citations

6