Nucleoporin 58

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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

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NUP58 Protein

Overview

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 structures

Nucleocytoplasmic 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 function

NUP58-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)

Overview

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)

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Nucleoporin 58

NUP58 Protein

Overview

Introduction

NUP58 Protein

Overview

Introduction

Structure

Domain Architecture

Key Structural Features

Normal Physiological Function

Nuclear Pore Complex Structure

Nucleocytoplasmic Transport

Cellular Functions

Role in Neurodegeneration

Amyotrophic Lateral Sclerosis (ALS)

Huntington's Disease

Cerebellar Ataxia

Alzheimer's Disease

Molecular Mechanisms

Transport Dysfunction Mechanisms

NUP58-NUP54 Interaction

Therapeutic Implications

Current Research Approaches

Challenges

Interacting Proteins

Nuclear Pore Complex Components

Transport Receptors

Disease-Associated Interactions

Key Publications

Signaling Pathways

See Also

Overview

Background

External Links

References