KEAP1 — Kelch-Like ECH-Associated Protein 1

KEAP1 — Kelch-Like ECH-Associated Protein 1

<div class="infobox infobox-protein">
<h3>KEAP1 Protein</h3>
<table>
<tr><th>Protein Name</th><td>Kelch-Like ECH-Associated Protein 1</td></tr>
<tr><th>Gene</th><td>[KEAP1](/genes/keap1)</td></tr>
<tr><th>UniProt ID</th><td>[Q14145](https://www.uniprot.org/uniprot/Q14145)</td></tr>
<tr><th>Molecular Weight</th><td>70 kDa</td></tr>
<tr><th>Subcellular Localization</th><td>Cytoplasm, Cytoskeleton</td></tr>
<tr><th>Protein Family</th><td>Kelch family</td></tr>
<tr><th>Gene Location</th><td>19p13.2</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">792 edges</a></td>
</tr>
</table>
</div>

Pathway Diagram

KEAP1 — Kelch-Like ECH-Associated Protein 1

<div class="infobox infobox-protein">
<h3>KEAP1 Protein</h3>
<table>
<tr><th>Protein Name</th><td>Kelch-Like ECH-Associated Protein 1</td></tr>
<tr><th>Gene</th><td>[KEAP1](/genes/keap1)</td></tr>
<tr><th>UniProt ID</th><td>[Q14145](https://www.uniprot.org/uniprot/Q14145)</td></tr>
<tr><th>Molecular Weight</th><td>70 kDa</td></tr>
<tr><th>Subcellular Localization</th><td>Cytoplasm, Cytoskeleton</td></tr>
<tr><th>Protein Family</th><td>Kelch family</td></tr>
<tr><th>Gene Location</th><td>19p13.2</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">792 edges</a></td>
</tr>
</table>
</div>

Pathway Diagram

Overview

KEAP1 (Kelch-Like ECH-Associated Protein 1) is a cysteine-rich adaptor protein that serves as the primary sensor of oxidative stress in cells[@keap2018][@keapnrf2020]. It functions as the negative regulator of NRF2 (Nuclear Factor Erythroid 2-Related Factor 2), the master transcription factor coordinating cellular antioxidant responses. The KEAP1-NRF2 pathway is one of the most important cellular defense mechanisms against oxidative damage and has been heavily implicated in neurodegenerative diseases including Alzheimer's, Parkinson's, and Huntington's disease[@keapnrf2021].

Structure

KEAP1 has a distinctive architecture with multiple functional domains:

• N-terminal region: Interacts with NRF2
• Broad complex, tramtrack, and bric à brac (BTB) domain: Mediates homodimerization andCul3 binding
• Intermediate region (IVR): Contains reactive cysteine residues
• Kelch repeat domain: Binds NRF2 Neh2 domain
• C-terminal region: Six kelch repeats forming a β-propeller

Normal Function

Oxidative Stress Sensing

KEAP1 functions as a molecular sensor:

• Cysteine oxidation: Reactive cysteines detect oxidative stress
• Conformational change: Oxidation disrupts KEAP1-NRF2 interaction
• NRF2 release: Freed NRF2 translocates to nucleus
• Transcriptional activation: NRF2 induces antioxidant genes

Protein Degradation

KEAP1 acts as a substrate adaptor:

• Cul3-RING ligase: Forms part of E3 ubiquitin ligase complex
• NRF2 ubiquitination: Targets NRF2 for degradation
• Proteasomal degradation: Maintains low NRF2 levels under basal conditions
• Turnover regulation: Controls NRF2 half-life

Cellular Homeostasis

The pathway regulates:

• Glutathione synthesis: Increases GSH production
• Detoxification enzymes: Induces phase I/II enzymes
• NAD(P)H regeneration: Enhances cellular reducing power
• Proteostasis: Regulates protein quality control

Role in Neurodegenerative Diseases

Alzheimer's Disease (AD)

KEAP1 dysregulation contributes to AD pathogenesis[@nrf2022]:

Parkinson's Disease (PD)

The pathway is critical in PD:

Huntington's Disease (HD)

KEAP1-NRF2 in HD:

Therapeutic Implications

KEAP1 is a major therapeutic target:

• NRF2 activators: Bardoxolone methyl and derivatives
• Cysteine-targeting compounds: Covalent KEAP1 modulators
• Gene therapy: NRF2 delivery approaches
• Preventive therapy: Antioxidant enhancement

Cross-links

• [KEAP1 Gene](/genes/keap1)
• [NRF2](/proteins/nrf2-protein)
• [Oxidative Stress](/mechanisms/oxidative-stress)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Antioxidant Response](/mechanisms/antioxidant-response)

See Also

• [NRF2](/entities/nrf2) — Transcription factor regulated by KEAP1
• [Oxidative Stress](/entities/oxidative-stress) — Pathological mechanism
• [Alzheimer's Disease](/diseases/alzheimers-disease) — Disease association
• [Parkinson's Disease](/diseases/parkinsons-disease) — Disease association
• [Neuroprotection](/entities/neuroprotection) - Protective mechanisms

External Links

• [KEAP1 - NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/9817) - Gene information
• [KEAP1 - UniProt](https://www.uniprot.org/uniprotkb/Q14145) - Protein data
• [KEAP1-NRF2 Pathway - Wikipedia](https://en.wikipedia.org/wiki/KEAP1-NRF2_pathway) - Pathway overview

References

Pathway Diagram

The following diagram shows the key molecular relationships involving KEAP1 — Kelch-Like ECH-Associated Protein 1 discovered through SciDEX knowledge graph analysis:

Expression Profile

Sources: [GTEx Portal v10](https://gtexportal.org/home/gene/keap1) | [Allen Brain Atlas](https://www.brain-map.org/)

GTEx Tissue Expression (median TPM)

| Rank | Tissue | Median TPM |
|------|--------|------------|
| 1 | Muscle Skeletal | 88.33 |
| 2 | Cervix Endocervix | 54.43 |
| 3 | Cells Cultured fibroblasts | 52.95 |
| 4 | Bladder | 51.91 |
| 5 | Esophagus Mucosa | 50.76 |
| 6 | Thyroid | 49.64 |
| 7 | Cervix Ectocervix | 48.50 |
| 8 | Uterus | 48.33 |
| 9 | Vagina | 47.36 |
| 10 | Skin Sun Exposed Lower leg | 44.67 |
| 11 | Brain Cerebellar Hemisphere | 44.02 |
| 12 | Prostate | 44.01 |
| 13 | Fallopian Tube | 43.47 |
| 14 | Colon Sigmoid | 42.73 |
| 15 | Nerve Tibial | 42.41 |

Brain-Region Expression:

| Region | Median TPM |
|--------|------------|
| Brain Cerebellar Hemisphere | 44.02 |
| Brain Cerebellum | 40.70 |