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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Strategies for the Nuclear Delivery of Metal Complexes to Cancer Cells

Advanced Materials, Год журнала: 2024, Номер 36(16)

Опубликована: Янв. 4, 2024

Abstract The nucleus is an essential organelle for the function of cells. It holds most genetic material and plays a crucial role in regulation cell growth proliferation. Since many antitumoral therapies target nucleic acids to induce death, tumor‐specific nuclear drug delivery could potentiate therapeutic effects prevent potential off‐target side on healthy tissue. Due their great structural variety, good biocompatibility, unique physico‐chemical properties, organometallic complexes other metal‐based compounds have sparked interest as promising anticancer agents. In this review, strategies specific metal are summarized discussed highlight parameters consider design new candidates. Moreover, existing opportunities challenges tumor‐specific, nucleus‐targeting emphasized outline some perspectives help cancer treatments.

Язык: Английский

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Conformational dynamics of the nuclear pore complex central channel

Biochemical Society Transactions, Год журнала: 2025, Номер 53(01)

Опубликована: Фев. 7, 2025

The nuclear pore complex (NPC) is a vital regulator of molecular transport between the nucleus and cytoplasm in eukaryotic cells. At heart NPC’s function are intrinsically disordered phenylalanineglycine-rich nucleoporins (FG-Nups), which form dynamic permeability barrier within central channel. This nature facilitates efficient nucleocytoplasmic but also poses significant challenges to its characterization, especially nano-confined environment NPC. Recent advances experimental techniques, such as cryo-electron microscopy, atomic force fluorescence magnetic resonance, along with computational modeling, have illuminated conformational flexibility FG-Nups, underpins their functional versatility. review synthesizes these advancements, emphasizing how disruptions FG-Nup behavior—caused by mutations or pathological interactions—contribute diseases neurodegenerative disorders, aging-related decline, viral infections. Despite progress, persist deciphering dynamics crowded cellular environment, under conditions. Addressing gaps critical for advancing therapeutic strategies targeting NPC dysfunction disease progression.

Язык: Английский

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Dynamic structure and function of nuclear pore protein complex: Potential roles of lipid and lamins regulated nuclear membrane curvature

International Journal of Biological Macromolecules, Год журнала: 2025, Номер unknown, С. 144104 - 144104

Опубликована: Май 1, 2025

Язык: Английский

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Nuclear Import and Export of YAP and TAZ

Cancers, Год журнала: 2023, Номер 15(20), С. 4956 - 4956

Опубликована: Окт. 12, 2023

Yes-associated Protein (YAP) and its paralog Transcriptional Coactivator with PDZ-binding Motif (TAZ) are major regulators of gene transcription/expression, primarily controlled by the Hippo pathway cytoskeleton. Integrating an array chemical mechanical signals, they impact growth, differentiation, regeneration. Accordingly, also play key roles in tumorigenesis metastasis formation. Their activity is regulated their localization, that is, pathway- and/or cytoskeleton-controlled cytosolic or nuclear sequestration. While many details such prevailing retention models have been elucidated, much less known about actual traffic: import export. Although size not far from cutoff for passive diffusion through pore complex (NPC), do contain any classic localization (NLS) export signal (NES), evidence has accumulating shuttling involves mediated thus regulatable/targetable processes. The aim this review to summarize emerging information/concepts nucleocytoplasmic shuttling, encompassing relevant structural requirements (NLS, NES), transport receptors (NTRs, karyophererins), NPC components, along potential mechanisms regulation. dissecting vs. often challenging, picture suggests YAP/TAZ shuttles across via multiple, non-exclusive, mechanisms, constituting a novel intriguing facet biology.

Язык: Английский

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Super-enhancer trapping by the nuclear pore via intrinsically disordered regions of proteins in squamous cell carcinoma cells

Cell chemical biology, Год журнала: 2023, Номер 31(4), С. 792 - 804.e7

Опубликована: Ноя. 3, 2023

Master transcription factors such as TP63 establish super-enhancers (SEs) to drive core transcriptional networks in cancer cells, yet the spatiotemporal regulation of SEs within nucleus remains unknown. The nuclear pore complex (NPC) may tether where RNA export rates are maximal. Here, we report that NUP153, a component NPC, anchors NPC and enhances expression by maximizing mRNA export. This anchoring is mediated through protein-protein interaction between intrinsically disordered regions (IDRs) NUP153 coactivator BRD4. Silencing excludes from periphery, decreases expression, impairs cellular growth, induces epidermal differentiation squamous cell carcinoma. Overall, this work reveals critical roles IDRs SE localization, thus providing insights into new layer gene at epigenomic spatial level.

Язык: Английский

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Integrative spatiotemporal map of nucleocytoplasmic transport

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 2, 2024

The Nuclear Pore Complex (NPC) facilitates rapid and selective nucleocytoplasmic transport of molecules as large ribosomal subunits viral capsids. It is not clear how key emergent properties this arise from the system components their interactions. To address question, we constructed an integrative coarse-grained Brownian dynamics model through a single NPC, followed by coupling it with kinetic Ran-dependent in entire cell. microscopic parameters were fitted to reflect experimental data theoretical information regarding transport, without making any assumptions about its properties. resulting reductionist validated reproducing several features used for construction, such morphology central transporter, rates passive facilitated diffusion function size valency, situ radial distributions pre-ribosomal subunits, active suggests that NPC functions essentially virtual gate whose flexible phenylalanine-glycine (FG) repeat proteins raise entropy barrier pore. Importantly, core functionality greatly enhanced design features, including 'fuzzy' transient interactions, multivalency, redundancy copy number FG nucleoporins, exponential kinetics thermodynamics accordance transition state theory, energy-reliant RanGTP concentration gradient. These result robust resilient rate selectivity wide array cargo ranging few kilodaltons megadaltons size. By dissecting these our provides quantitative starting point rationally modulating artificial mimics.

Язык: Английский

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Deciphering the intrinsically disordered characteristics of the FG-Nups through the lens of polymer physics

Nucleus, Год журнала: 2024, Номер 15(1)

Опубликована: Сен. 16, 2024

The nuclear pore complex (NPC) is a critical gateway regulating molecular transport between the nucleus and cytoplasm. It allows small molecules to pass freely, while larger require receptors traverse barrier. This selective permeability maintained by phenylalanine-glycine-rich nucleoporins (FG-Nups), intrinsically disordered proteins that fill NPC's central channel. flexible nature of FG-Nups complicates their spatial characterization with conventional structural biology techniques. To address this challenge, polymer physics offers valuable framework for describing FG-Nup behavior, reducing structures few key parameters. In review, we explore how models using these parameters discuss experimental efforts quantify them in various contexts, providing insights into conformational properties FG-Nups.

Язык: Английский

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Role of pore dilation in molecular transport through the nuclear pore complex: Insights from polymer scaling theory

PLoS Computational Biology, Год журнала: 2025, Номер 21(4), С. e1012909 - e1012909

Опубликована: Апрель 7, 2025

The nuclear pore complex (NPC), a channel within the envelope filled with intrinsically disordered proteins, regulates transport of macromolecules between nucleus and cytoplasm. Recent studies have highlighted NPC’s ability to adjust its diameter in response membrane tension, underscoring importance exploring how variations size influence molecular through NPC. In this study, we investigated relationship rate proposed mathematical model describing connection. We began by theoretically analyzing scales characteristic dimensions mesh-like structure pore. By introducing key assumptions about meshwork influences diffusion, derived expression for based on transported molecules. To validate our model, conducted Brownian dynamics simulations using coarse-grained representation These simulations, performed across range sizes, demonstrated strong agreement model’s predictions, confirming accuracy applicability. Our is specifically tailored small-to-medium-sized molecules, approximately 5 nanometers size, making it relevant wide transcription factors signaling It also extends molecules weak transient interactions FG-Nups, such as importin- β . presenting formula, study offers quantitative framework effects dilation nucleocytoplasmic transport.

Язык: Английский

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Elucidating the nanoscopic organization and dynamics of the nuclear pore complex

Nucleus, Год журнала: 2025, Номер 16(1)

Опубликована: Июнь 4, 2025

Due to its pivotal role as a regulator of nucleocytoplasmic transport, the structure and dynamic gating mechanism nuclear pore complex (NPC) is subject immense interest. Here, we report key recent advancements discussed at Selective Transport Control in Biological Biomimetic Nanopores meeting (Monte Verità, Switzerland, 2024) that gathered NPC experts from range disciplines. Novel insights were reported cutting-edge super-resolution techniques enable direct interrogation NPC's central transporter; computational models unravel mechanisms selective barrier; synthetic mimics valuable vitro for delineating permeability transport dynamics. Altogether, three major highlighted: (i) presence dynamically organised pathways within NPC, (ii) receptors enrich reinforce barrier, (iii) ability DNA origami nanostructures mimic aspects with unprecedented precision. Overall, marked convergence our understanding function by unraveling nanoscale.

Язык: Английский

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