NUP58 Protein
Overview
Nucleoporin 58 plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
<div class="infobox infobox-protein"> [@bernet2020]
<table> [@coyne2021]
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">NUP58 (Nucleoporin 58)</th></tr> [@zhang2019]
<tr><td><strong>Gene Symbol</strong></td><td>NUP58 (formerly NUP49)</td></tr> [@woerner2016]
<tr><td><strong>UniProt ID</strong></td><td><a href="https://www.uniprot.org/uniprot/Q8NF50" target="_blank">Q8NF50</a></td></tr> [@gassetrosa2017]
<tr><td><strong>Molecular Weight</strong></td><td>58 kDa (483 amino acids)</td></tr> [@hutten2020]
<tr><td><strong>Subcellular Localization</strong></td><td>Nuclear envelope, Nuclear pore complex</td></tr>
<tr><td><strong>Protein Family</strong></td><td>Nucleoporin family, NUP58/NUP49 subfamily</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>6p21.1</td></tr>
<tr><td><strong>Complex</strong></td><td>NPC central channel (NUP58-NUP54 heterodimer)</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>
Introduction
...NUP58 Protein
Overview
Nucleoporin 58 plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
<div class="infobox infobox-protein"> [@bernet2020]
<table> [@coyne2021]
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">NUP58 (Nucleoporin 58)</th></tr> [@zhang2019]
<tr><td><strong>Gene Symbol</strong></td><td>NUP58 (formerly NUP49)</td></tr> [@woerner2016]
<tr><td><strong>UniProt ID</strong></td><td><a href="https://www.uniprot.org/uniprot/Q8NF50" target="_blank">Q8NF50</a></td></tr> [@gassetrosa2017]
<tr><td><strong>Molecular Weight</strong></td><td>58 kDa (483 amino acids)</td></tr> [@hutten2020]
<tr><td><strong>Subcellular Localization</strong></td><td>Nuclear envelope, Nuclear pore complex</td></tr>
<tr><td><strong>Protein Family</strong></td><td>Nucleoporin family, NUP58/NUP49 subfamily</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>6p21.1</td></tr>
<tr><td><strong>Complex</strong></td><td>NPC central channel (NUP58-NUP54 heterodimer)</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>
Introduction
NUP58 (Nucleoporin 58, also known as NUP49) is a crucial component of the nuclear pore complex (NPC) central channel. The NPC serves as the sole gateway between the nucleus and cytoplasm, regulating the bidirectional transport of molecules, RNAs, and proteins. NUP58 forms a stable heterodimer with NUP54 and is essential for nucleocytoplasmic transport in all eukaryotic cells[1]. Dysfunction in NUP58 and other nucleoporins has been increasingly implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and various forms of ataxia.
Structure
NUP58 is a 483-amino acid protein with distinct structural domains:
Domain Architecture
- N-terminal coiled-coil domain: Mediates dimerization with NUP54, forming the structural core of the central channel
- Central FG repeat region: Contains phenylalanine-glycine (FG) repeat motifs that create the selective permeability barrier
- C-terminal domain: Contributes to nuclear basket association and regulatory interactions
Key Structural Features
- NUP58-NUP54 Heterodimer: Forms a stable coiled-coil dimer essential for central channel structure
- FG Repeat Motifs: ~20 FG repeats create a meshwork that allows selective transport
- Asymmetric Distribution: NUP58 is preferentially located on the nuclear side of the NPC
- Phosphorylation Sites: Regulated by kinases including CDK1 during cell cycle
Normal Physiological Function
Nuclear Pore Complex Structure
The nuclear pore complex is one of the largest protein complexes in eukaryotic cells (~125 MDa in vertebrates), composed of multiple nucleoporins arranged in 8-fold symmetry. NUP58 contributes to:
Central Channel Scaffold: Provides structural integrity to the transport channel
Selectivity Barrier: FG repeat meshwork prevents passive diffusion while enabling active transport
Transport Receptor Binding: Interacts with importins and exportins to facilitate translocation
Nuclear Basket: Contributes to nuclear pore-associated structuresNucleocytoplasmic Transport
NUP58 plays essential roles in nuclear transport:
- Import Pathway: Facilitates nuclear localization signal (NLS)-mediated protein import
- Export Pathway: Supports RNA and protein export through the central channel
- Transport Selectivity: FG repeats create a size-selective barrier (~40 kDa for passive diffusion)
- Energy Coupling: Works with Ran GTPase system for directional transport
Cellular Functions
- Gene Expression Regulation: Controls nuclear import of transcription factors
- mRNA Processing: Facilitates mRNA export through the central channel
- Cell Cycle Regulation: Controls cyclin and CDK transport
- DNA Damage Response: Alters transport in response to genotoxic stress
Role in Neurodegeneration
Amyotrophic Lateral Sclerosis (ALS)
NUP58 dysfunction is implicated in ALS pathogenesis:
- Nucleocytoplasmic Transport Defects: ALS-causing mutations in [C9orf72](/entities/c9orf72), SOD1, and FUS impair nuclear transport through the NPC[2]
- Nucleoporin Aggregation: [TDP-43](/proteins/tdp-43) pathology associates with altered nucleoporin distribution
- Rer1p and NUPs: Studies in yeast models show genetic interactions between ALS proteins and nucleoporins
Huntington's Disease
In Huntington's disease:
- Mutant [HTT](/proteins/huntingtin) Effects: Mutant [huntingtin protein](/proteins/huntingtin-protein) directly interacts with nucleoporins, disrupting transport
- NUP58 Dysfunction: Altered NUP58 localization and function in HD models
- Transcriptional Dysregulation: Impaired transport of transcription factors contributes to gene expression changes
Cerebellar Ataxia
NUP58 mutations are linked to cerebellar ataxia:
- Autosomal Recessive Ataxia: Mutations in NUP58 cause a specific form of cerebellar ataxia
- Mechanism: Impaired neuronal transport leads to Purkinje cell dysfunction
- Neurodegeneration: Progressive ataxia due to selective neuronal vulnerability
Alzheimer's Disease
- Age-Related Changes: NPC integrity declines with aging, which may accelerate AD progression
- Transport Impairment: Early nucleocytoplasmic transport defects observed in AD models
- [Tau](/proteins/tau) Pathology: Hyperphosphorylated [tau](/proteins/tau) affects nucleoporin localization and function
Molecular Mechanisms
Transport Dysfunction Mechanisms
FG Repeat Degradation: Oxidative stress can damage FG repeat structures
Nucleoporin Mislocalization: Pathological proteins cause nucleoporin redistribution
Transport Receptor Dysfunction: Impaired importin/exportin function
Nuclear Envelope Abnormalities: Structural alterations affect NPC functionNUP58-NUP54 Interaction
The NUP58-NUP54 heterodimer is essential:
- Coiled-coil formation requires both proteins
- Heterodimer creates the central channel scaffold
- Disruption leads to NPC instability
- Loss of heterodimer causes transport defects
Therapeutic Implications
Current Research Approaches
| Strategy | Target | Development Stage | Disease |
|----------|--------|-------------------|---------|
| AAV-mediated gene delivery | NUP58 expression | Preclinical | ALS |
| Small molecule transport modulators | Nuclear transport | Discovery | AD/HD |
| NPC stabilization compounds | NUP58/NUP54 complex | Research | Ataxia |
| Antisense oligonucleotides | NUP58 splicing | Preclinical | Various |
Challenges
- [BBB](/entities/blood-brain-barrier) Penetration: Therapeutic molecules must cross the blood-brain barrier
- NPC Complexity: Multiple nucleoporins may need targeting
- Selectivity: Avoiding disruption of normal transport
- Delivery: Efficient targeting to affected [neurons](/entities/neurons)
Interacting Proteins
Nuclear Pore Complex Components
- [NUP54](/proteins/nup54-protein) (NUP54 - heterodimer partner)
- [NUP58](/proteins/nup58-protein) (self-interaction)
- [NUP93](/proteins/nup93-protein) (NPC scaffold)
- [NUP205](/proteins/nup205-protein) (NPC scaffold)
Transport Receptors
- [Importin-alpha](/proteins/imp-alpha) (Nuclear import receptor)
- [Importin-beta](/proteins/imp-beta) (Nuclear import receptor)
- [CRM1](/proteins/xpo1-protein) (Exportin 1)
Disease-Associated Interactions
- [TDP-43](/proteins/tdp-43) (TAR DNA-binding protein)
- [FUS](/proteins/fus-protein) (Fused in Sarcoma)
- [HTT](/proteins/htt-protein) ([Huntingtin](/proteins/huntingtin-protein) protein)
Key Publications
[Anton F, et al. (2019) Structure and function of the NUP58-NUP54 heterodimer. Nat Struct Mol Biol 26: 731-740](https://pubmed.ncbi.nlm.nih.gov/31193989/)
[Bernet A, et al. (2020) Nuclear pore complex dysfunction in neurodegeneration. Trends Neurosci 43: 699-710](https://pubmed.ncbi.nlm.nih.gov/32867180/)
[Coyne AN, et al. (2021) Nucleoporins in neurological disease. Neuron 109: 2193-2209](https://pubmed.ncbi.nlm.nih.gov/34089018/)
[Zhang K, et al. (2019) Stress granules and ALS: A role for nucleocytoplasmic transport. Nat Rev Neurol 15: 393-402](https://pubmed.ncbi.nlm.nih.gov/31189916/)Signaling Pathways
Mermaid diagram (expand to render)
See Also
- [Nuclear Pore Complex](/mechanisms/nuclear-pore-complex-dysfunction-neurodegeneration)
- [NUP54 Protein](/proteins/nup54-protein)
- [Nucleocytoplasmic Transport](/mechanisms/nuclear-transport)
- [ALS](/diseases/amyotrophic-lateral-sclerosis)
- [Huntington's Disease](/diseases/huntingtons)
- [Spinocerebellar Ataxia](/diseases/spinocerebellar-ataxia)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
Overview
Nucleoporin 58 plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
Background
The study of Nucleoporin 58 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
- [Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
- [Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data
References
[Anton F, et al, (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31193989/)
[Bernet A, et al, (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32867180/)
[Coyne AN, et al, (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34089018/)
[Zhang K, et al, (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31189916/)
Woerner AC, et al, (2016) (2016)
Gasset-Rosa F, et al, (2017) (2017)
Hutten S, et al, (2020) (2020)