VHL Protein
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">VHL Protein</th>
</tr>
<tr> [@lee2015]
<td class="label">Gene</td> [@siddiq2009]
<td>[VHL](/genes/vhl)</td> [@gossage2010]
</tr> [@bernhardt2006]
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P40337" target="_blank">P40337</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td>1LM8, 1VCB, 4BJC</td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>19.5 kDa (pVHL30), 13.2 kDa (pVHL19)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Cytoplasm; nucleus under certain conditions</td>
</tr>
<tr>
<td class="label">Family</td>
<td>VHL tumor suppressor family</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), [Stroke](/diseases/stroke), [Huntington's Disease](/diseases/huntingtons)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/cardiac" style="color:#ef9a9a">Cardiac</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">196 edges</a></td>
</tr>
</table>
VHL Protein
Introduction
...VHL Protein
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">VHL Protein</th>
</tr>
<tr> [@lee2015]
<td class="label">Gene</td> [@siddiq2009]
<td>[VHL](/genes/vhl)</td> [@gossage2010]
</tr> [@bernhardt2006]
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P40337" target="_blank">P40337</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td>1LM8, 1VCB, 4BJC</td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>19.5 kDa (pVHL30), 13.2 kDa (pVHL19)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Cytoplasm; nucleus under certain conditions</td>
</tr>
<tr>
<td class="label">Family</td>
<td>VHL tumor suppressor family</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), [Stroke](/diseases/stroke), [Huntington's Disease](/diseases/huntingtons)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/cardiac" style="color:#ef9a9a">Cardiac</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">196 edges</a></td>
</tr>
</table>
VHL Protein
Introduction
Vhl Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Overview
VHL (Von Hippel-Lindau tumor suppressor) protein is encoded by the [VHL](/genes/vhl) gene. It belongs to the VHL tumor suppressor family and has a molecular weight of approximately 19.5 kDa (pVHL30 isoform)^[@kaelin2008]. This protein is localized to Cytoplasm; nucleus under certain conditions and plays a significant role in the pathogenesis of [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), [Stroke](/diseases/stroke), [Huntington's Disease](/diseases/huntingtons).
Structure
The VHL protein has been characterized structurally through X-ray crystallography. Available PDB structures include: 1LM8, 1VCB, 4BJC^[@stebbins1999].
The protein's three-dimensional structure can also be explored via the [AlphaFold Protein Structure Database](https://alphafold.ebi.ac.uk/entry/P40337).
Normal Function
Under physiological conditions, VHL performs essential functions in the nervous system. It is primarily found in Cytoplasm; nucleus under certain conditions and contributes to normal cellular homeostasis, signaling, and neuronal function.
HIF Regulation
The primary function of VHL is as the substrate recognition component of an E3 ubiquitin ligase complex that targets hypoxia-inducible factor-alpha (HIF-α) for degradation:
- Normoxia: VHL binds hydroxylated HIF-α, leading to ubiquitination and proteasomal degradation
- Hypoxia: HIF-α escapes VHL recognition, accumulates, and activates transcription of adaptive genes
- Target genes: VEGF (angiogenesis), EPO (erythropoiesis), GLUT1 (glucose transport), and more
Additional Functions
- Extracellular matrix maintenance and fibronectin assembly
- Microtubule stabilization
- Primary cilia formation
- DNA damage response
Role in Disease
VHL is implicated in the following neurodegenerative conditions:
- [Alzheimer's Disease](/diseases/alzheimers-disease) — Hypoxia and impaired HIF response contribute to [Aβ](/proteins/amyloid-beta) pathology and neuronal energy failure
- [Parkinson's Disease](/diseases/parkinsons-disease) — Dopaminergic [neurons](/entities/neurons) vulnerable to hypoxia; VHL/HIF pathway affects mitochondrial function
- [Stroke](/diseases/stroke) — Acute hypoxia activates HIF pathway; VHL deletion is protective in experimental stroke
- [Huntington's Disease](/diseases/huntingtons) — Mutant [huntingtin](/proteins/huntingtin) impairs HIF1A transactivation
Misfolding, aggregation, or dysfunction of VHL contributes to neuronal damage through various mechanisms including impaired hypoxia response, disrupted cellular signaling, and neuroinflammation.
Therapeutic Targeting
VHL represents an important therapeutic target. Multiple drug development programs are exploring strategies to modulate its function:
- HIF prolyl hydroxylase inhibitors (e.g., roxadustat, vadadustat): Increase HIF activity for neuroprotection
- VHL-HIF interaction modulators: Small molecules targeting the VHL-HIF interface
- Gene therapy: HIF1A or VHL gene delivery approaches
External Links
- UniProt: [https://www.uniprot.org/uniprot/P40337](https://www.uniprot.org/uniprot/P40337)
- AlphaFold: [VHL Protein](https://alphafold.ebi.ac.uk/entry/P40337)
- PDB: [1LM8](https://www.rcsb.org/structure/1LM8), [1VCB](https://www.rcsb.org/structure/1VCB), [4BJC](https://www.rcsb.org/structure/4BJC)
See Also
- [Proteins Index](/proteins)
- [Genes Index](/genes)
- [Diseases Index](/diseases)
- [Mechanisms Index](/mechanisms)
- [Hypoxia Response](/mechanisms/hypoxia-response)
Brain Atlas Resources
- Allen Human Brain Atlas: [VHL expression search](https://human.brain-map.org/microarray/search/show?search_term=VHL)
- Allen Mouse Brain Atlas: [VHL search](https://mouse.brain-map.org/search/index.html?query=VHL)
- Allen Cell Type Atlas: [Transcriptomic cell type reference](https://portal.brain-map.org/atlases-and-data/rnaseq)
- BrainSpan Developmental Transcriptome: [VHL developmental expression](https://www.brainspan.org/rnaseq/search/index.html?search_term=VHL)
Background
The study of Vhl Protein 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.
References
[Kaelin WG, (2008) (2008)](https://doi.org/10.1038/nrc2501)
[Stebbins CE, Kaelin WG Jr, Pavletich NP, (1999) (1999)](https://doi.org/10.1126/science.284.5413.455)
[Schofield CJ, Ratcliffe PJ, (2004) (2004)](https://doi.org/10.1038/nrm1362)
[Li L, et al, (2009) (2009)](https://doi.org/10.3233/JAD-2009-1069)
[Lee DW, et al, (2015) (2015)](https://doi.org/10.1007/978-3-319-09581-3_4)
[Siddiq A, et al, (2009) (2009)](https://doi.org/10.1016/j.brainres.2009.06.052)
[Gossage L, Eisen T, (2010) (2010)](https://doi.org/10.1038/nrc2773)
[Bernhardt WM, et al, (2006) (2006)](https://doi.org/10.1038/nrc1924)