NCOA4 Protein

NCOA4 Protein

Pathway Diagram

```mermaid
flowchart TD
NCOA4["NCOA4<br/>Nuclear Receptor<br/>Coactivator 4"]

Ferritinophagy["Ferritinophagy<br/>Iron Release from<br/>Ferritin"]

Iron_Pool["Cellular Iron<br/>Pool"]

GPX4["GPX4<br/>Glutathione<br/>Peroxidase 4"]

Ferroptosis["Ferroptosis<br/>Iron-dependent<br/>Cell Death"]

SLC7A11["SLC7A11<br/>Cystine/Glutamate<br/>Antiporter"]

Autophagy["Autophagy<br/>Pathway"]

ALS["Amyotrophic<br/>Lateral Sclerosis"]

MS["Multiple<br/>Sclerosis"]

Parkinsons["Parkinson's<br/>Disease"]

Neurodegeneration["Neuronal<br/>Death"]

Oxidative_Stress["Oxidative<br/>Stress"]

Iron_Homeostasis["Iron<br/>Homeostasis<br/>Disruption"]

Therapeutic_Target["Therapeutic<br/>Intervention<br/>Target"]

NCOA4 -->|"mediates"| Ferritinophagy
Ferritinophagy -->|"releases"| Iron_Pool
Iron_Pool -->|"promotes"| Oxidative_Stress
NCOA4 -->|"inhibits"| GPX4
GPX4 -->|"protects_against"| Ferroptosis
NCOA4 -->|"regulates"| Ferroptosis
Iron_Pool -->|"drives"| Ferroptosis
SLC7A11 -->|"inhibits"| Ferroptosis
NCOA4 -->|"regulates"| Autophagy
Ferroptosis -->|"causes"| Neurodegeneration
Oxidative_Stress -->|"leads_to"| Neurodegeneration
NCOA4 -->|"activates"| ALS
NCOA4 -->|"regulates"| MS
NCOA4 -->|"associated_with"| Parkinsons
ALS -->|"involves"| Neurodegeneration
MS -->|"involves"| Neurodegeneration
Parkinsons -->|"involves"| Neurodegeneration
Iron_Pool -->|"disrupts"| Iron_Homeostas

NCOA4 Protein

Pathway Diagram

title: NCOA4 Protein

NCOA4 Protein (Nuclear Receptor Coactivator 4)

Overview

NCOA4 is a selective cargo receptor for ferritinophagy, the autophagic degradation of ferritin. This protein plays a critical role in cellular iron homeostasis by mediating the release of iron from ferritin storage, and is essential for preventing iron accumulation in the brain that leads to neurodegenerative diseases. [@kohan2015]

Introduction

NCOA4 (Nuclear Receptor Coactivator 4) was originally characterized as a transcriptional coactivator for nuclear receptors, but has gained prominence as the primary receptor mediating ferritinophagy. As a selective [autophagy](/entities/autophagy) receptor, NCOA4 binds ferritin and delivers it to autophagosomes for lysosomal degradation, releasing stored iron for cellular use.

<div class="infobox infobox-protein">

| Property | Value |
|----------|-------|
| Protein Name | NCOA4 (Nuclear Receptor Coactivator 4) |
| Gene | [NCOA4](/genes/ncoa4) |
| UniProt ID | Q9UBR1 |
| PDB Structure | 6GJA (N-terminal domain) |
| Molecular Weight | ~70 kDa |
| Subcellular Localization | Cytoplasmic, nuclear (shuttling) |
| Protein Family | Nuclear receptor coactivator family |

</div>

Structure

NCOA4 has a multi-domain structure:

N-Terminal Domain

• Contains the ferritin-binding site
• Essential for ferritinophagy function
• Mediates interaction with autophagic machinery

C-Terminal Domain

• Transcriptional activation domain
• Nuclear receptor interaction motifs
• LXXLL motifs for coactivator function

Key Structural Features

• Coiled-coil domains for protein interactions
• LC3-interacting region (LIR) for autophagy
• Multiple post-translational modification sites

Normal Function

Ferritinophagy (Primary Neurodegeneration-Relevant Function)

• Binds to ferritin (FTH1/FTL complex)
• Recruits the autophagic machinery via LC3 interaction
• Delivers ferritin to autophagosomes
• Releases iron from ferritin for cellular use

Transcriptional Coactivation

• Coactivator for nuclear receptors
• Binds thyroid hormone receptors, retinoic acid receptors
• Recruits CBP/p300 coactivators
• Regulates metabolism and development genes

Role in Disease

Alzheimer's Disease

• Ferritinophagy is impaired in AD brains
• Iron accumulates in [neurons](/entities/neurons) and amyloid plaques
• Dysregulated NCOA4 contributes to oxidative stress
• Therapeutic targeting is under investigation

Parkinson's Disease

• Iron accumulates in substantia nigra dopaminergic neurons
• NCOA4 deficiency leads to iron overload
• Implicated in PD pathogenesis
• Iron chelation may work partly through ferritinophagy

Neurodegeneration with Brain Iron Accumulation (NBIA)

• NCOA4 variants cause certain NBIA subtypes
• Impaired ferritinophagy leads to iron accumulation
• Presents with movement disorders and dementia

Therapeutic Targeting

Small Molecule Activators

• Compounds that enhance ferritinophagy
• Could reduce iron accumulation in neurodegeneration
• Currently in preclinical development

Gene Therapy Approaches

• Viral vector delivery of NCOA4
• Under investigation for NBIA treatment

Key Publications

Cross-Links

• [NCOA4 Gene](/genes/ncoa4) - Encoding gene
• [Ferritin](/proteins/ferritin) - Primary cargo
• [Iron homeostasis](/mechanisms/iron-homeostasis) - Pathway
• [Ferroptosis](/mechanisms/ferroptosis) - Cell death pathway
• [Autophagy](/mechanisms/autophagy) - Cellular process
• [Alzheimer's disease](/diseases/alzheimers-disease) - Disease link
• [Parkinson's disease](/diseases/parkinsons-disease) - Disease link

See Also

• [Neurodegeneration](/diseases/neurodegeneration) — General mechanisms

External Links

• [UniProt](https://www.uniprot.org/)

References