UBE2K Protein

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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

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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.

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/)

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/)

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UBE2K Protein

UBE2K Protein (E2 K)

Introduction

Overview

UBE2K Protein (E2 K)

Introduction

Overview

Structure

Normal Function

Ubiquitin Conjugation

DNA Damage Response

Protein Quality Control

Inflammatory Signaling

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

Huntington's Disease

Therapeutic Implications

Animal Models

Key Publications

See Also

External Links

Background

References