UBE2K Protein (E2 K)
Introduction
Ube2K 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.
<div class="infobox infobox-protein">
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<tr><th colspan="2" style="background:#4a90d9; color:white;">Ubiquitin-Conjugating Enzyme E2 K (UBE2K)</th></tr>
<tr><td><strong>Gene</strong></td><td>[UBE2K](/genes/ube2k)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[P61006](https://www.uniprot.org/uniprot/P61006)</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>22 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Cytoplasm, nucleus</td></tr>
<tr><td><strong>Protein Family</strong></td><td>E2 ubiquitin-conjugating enzyme family</td></tr>
<tr><td><strong>EC Number</strong></td><td>2.3.2.23</td></tr>
<tr><td><strong>Aliases</strong></td><td>E2-25K, HIP2, Ubc13</td></tr>
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<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
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Overview
...UBE2K Protein (E2 K)
Introduction
Ube2K 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.
<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#4a90d9; color:white;">Ubiquitin-Conjugating Enzyme E2 K (UBE2K)</th></tr>
<tr><td><strong>Gene</strong></td><td>[UBE2K](/genes/ube2k)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[P61006](https://www.uniprot.org/uniprot/P61006)</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>22 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Cytoplasm, nucleus</td></tr>
<tr><td><strong>Protein Family</strong></td><td>E2 ubiquitin-conjugating enzyme family</td></tr>
<tr><td><strong>EC Number</strong></td><td>2.3.2.23</td></tr>
<tr><td><strong>Aliases</strong></td><td>E2-25K, HIP2, Ubc13</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>
Overview
UBE2K (Ubc13/UEV1) is an E2 ubiquitin-conjugating enzyme that catalyzes the formation of K63-linked polyubiquitin chains. Originally identified as HGS-HIP2 (hepatocyte growth factor-regulated tyrosine kinase substrate), UBE2K plays critical roles in DNA repair, signal transduction, protein quality control, and inflammatory responses[@wu2006][@hofmann2001]. Unlike classical E2 enzymes that generate K48-linked chains for proteasomal degradation, UBE2K specifically produces K63-linked chains that serve non-degradative signaling functions.
Structure
UBE2K contains several distinct structural features:
- UBC Domain: The catalytic core (~150 amino acids) contains the active site cysteine (Cys-92) required for ubiquitin thioester formation
- UEV1 Motif: A variant E2 domain at the N-terminus that lacks the catalytic cysteine but facilitates substrate recognition
- Flexible N- and C-termini: These regions contain regulatory phosphorylation sites and protein-protein interaction domains
- Dimerization Interface: UBE2K can form homodimers, which is important for its enzymatic activity
The three-dimensional structure reveals a characteristic α/β fold common to E2 enzymes, with a central β-sheet surrounded by α-helices.
Normal Function
UBE2K participates in multiple cellular pathways through its ability to generate K63-linked polyubiquitin chains:
Ubiquitin Conjugation
UBE2K works in conjunction with the E3 ligase TRAF6 to catalyze K63-linked polyubiquitin chain formation. This modification does not target proteins for degradation but instead serves as a signaling platform for various cellular processes[@deng2010].
DNA Damage Response
UBE2K is involved in the ATM/ATR-mediated DNA damage response pathway. Following genotoxic stress, UBE2K contributes to the activation of [NF-κB](/entities/nf-kb) and downstream anti-apoptotic gene expression.
Protein Quality Control
The enzyme participates in the clearance of misfolded proteins and protein aggregates through the [ubiquitin-proteasome system](/cell-types/ubiquitin-proteasome-system) and selective [autophagy](/entities/autophagy) pathways.
Inflammatory Signaling
UBE2K-mediated ubiquitination is essential for proper activation of innate immune signaling, including TLR and NLR receptor pathways.
Role in Neurodegeneration
Alzheimer's Disease
In AD, UBE2K plays a dual role in both promoting and potentially protecting against pathology:
- The ubiquitin-proteasome system is compromised in AD brains, and UBE2K activity may be reduced
- K63-linked ubiquitination is involved in [tau](/proteins/tau) phosphorylation and aggregation pathways
- UBE2K has been shown to interact with [amyloid precursor protein](/entities/app-protein) (APP) processing[@el2019]
Parkinson's Disease
- UBE2K is implicated in [α-synuclein](/proteins/alpha-synuclein) clearance pathways
- Genetic studies have identified UBE2K variants associated with PD risk
- The enzyme contributes to mitophagy through Parkin-independent mechanisms
Amyotrophic Lateral Sclerosis (ALS)
- UBE2K is involved in the clearance of mutant SOD1 aggregates
- [TDP-43](/proteins/tdp-43) proteinopathy may involve altered UBE2K-mediated ubiquitination
- The enzyme participates in stress granule dynamics
Huntington's Disease
- Mutant [huntingtin](/proteins/huntingtin-protein) protein is modified by K63-linked ubiquitin chains
- UBE2K may facilitate the clearance of mutant [HTT](/genes/htt) aggregates
- Altered ubiquitination patterns are observed in HD patient brains
Therapeutic Implications
UBE2K represents a potential therapeutic target for neurodegenerative diseases:
| Strategy | Approach | Status |
|----------|----------|--------|
| Small molecule activators | Enhance UBE2K activity to improve protein clearance | Preclinical |
| Gene therapy | Overexpress UBE2K to boost [UPS](/cell-types/ubiquitin-proteasome-system) function | Research |
| Modulators | Develop compounds that enhance K63-linked ubiquitination | Early research |
Animal Models
- Ube2k knockout mice: Exhibit embryonic lethality, highlighting its essential role
- Conditional knockouts: Used to study role in specific neuronal populations
- Drosophila homolog: `bendless` (ubl) is involved in synaptic plasticity
Key Publications
Wu PY, et al. Ubc13 in signaling and disease. Cell Mol Life Sci. 2006;63(23):2667-2675. PMID: 17063477(https://pubmed.ncbi.nlm.nih.gov/17063477/)
Hofmann RM, Pickart CM. Ubc13 in ubiquitin chain synthesis. Cell. 2001;105(5):575-585. PMID: 11389828(https://pubmed.ncbi.nlm.nih.gov/11389828/)
Deng L, et al. Regulation of NF-κB signaling by Lys63-linked ubiquitination. Cell Res. 2010;20(9):1003-1021. PMID: 20729854(https://pubmed.ncbi.nlm.nih.gov/20729854/)
El Ayadi A, et al. Ubiquitin-conjugating enzymes in neurodegeneration. Biochim Biophys Acta. 2019;1866(4):713-731. PMID: 30685457(https://pubmed.ncbi.nlm.nih.gov/30685457/)See Also
- [UBE2K Gene](/proteins/ube2k-protein)
- [Ubiquitin-Proteasome System](/cell-types/ubiquitin-proteasome-system)
- [K63-Linked Ubiquitination](/mechanisms/k63-ubiquitination)
- [Protein Quality Control](/mechanisms/protein-quality-control-network)mechanisms/protein-quality-control-network)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Amyotrophic Lateral Sclerosis](/diseases/als)
- [Huntington's Disease](/diseases/huntingtons)
External Links
- [UniProt: P61006](https://www.uniprot.org/uniprot/P61006)
- [PDB: 1ZDN](https://www.rcsb.org/structure/1ZDN)
- [NCBI Gene: 9352](https://www.ncbi.nlm.nih.gov/gene/9352)
Background
The study of Ube2K 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
[Wu PY, et al, Ubc13 in signaling and disease (2006)](https://pubmed.ncbi.nlm.nih.gov/17063477/)
[Hofmann RM, Pickart CM, Ubc13 in ubiquitin chain synthesis (2001)](https://pubmed.ncbi.nlm.nih.gov/11389828/)
[Deng L, et al, Regulation of NF-κB signaling by Lys63-linked ubiquitination (2010)](https://pubmed.ncbi.nlm.nih.gov/20729854/)
[El Ayadi A, et al, Ubiquitin-conjugating enzymes in neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/30685457/)