UBE2A Protein

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UBE2A Protein

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UBE2A Protein

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">UBE2A Protein</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Ubiquitin-Conjugating Enzyme E2 A</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>UBE2A</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P49411</td>
</tr>
<tr>
<td class="label">PDB Structure IDs</td>
<td>1X23, 2YJA, 4LJP</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>17 kDa</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Nucleus, Cytoplasm</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Ubiquitin-conjugating enzyme (E2) family</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>RAD6A, UbcH2</td>
</tr>
<tr>
<td class="label">E3 Ligase</td>
<td>Function</td>
</tr>
<tr>
<td class="label">RNF10</td>
<td>Synaptic protein ubiquitination</td>
</tr>
<tr>
<td class="label">RNF14</td>
<td>Transcriptional regulation</td>
</tr>
<tr>
<td class="label">RNF138</td>
<td>DNA repair coordination</td>
</tr>
<tr>
<td class="label">HERC2</td>
<td>Protein quality control</td>
</tr>
<tr>
<td class="label">Parkin</td>
<td>Mitophagy pathway</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

...

UBE2A Protein

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">UBE2A Protein</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Ubiquitin-Conjugating Enzyme E2 A</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>UBE2A</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P49411</td>
</tr>
<tr>
<td class="label">PDB Structure IDs</td>
<td>1X23, 2YJA, 4LJP</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>17 kDa</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Nucleus, Cytoplasm</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Ubiquitin-conjugating enzyme (E2) family</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>RAD6A, UbcH2</td>
</tr>
<tr>
<td class="label">E3 Ligase</td>
<td>Function</td>
</tr>
<tr>
<td class="label">RNF10</td>
<td>Synaptic protein ubiquitination</td>
</tr>
<tr>
<td class="label">RNF14</td>
<td>Transcriptional regulation</td>
</tr>
<tr>
<td class="label">RNF138</td>
<td>DNA repair coordination</td>
</tr>
<tr>
<td class="label">HERC2</td>
<td>Protein quality control</td>
</tr>
<tr>
<td class="label">Parkin</td>
<td>Mitophagy pathway</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Ubiquitin-Conjugating Enzyme E2 A (UBE2A), also known as RAD6A, is a 17 kDa enzyme that catalyzes the conjugation of ubiquitin to target proteins. This member of the E2 ubiquitin-conjugating enzyme family plays essential roles in protein quality control, DNA repair, and synaptic function. UBE2A has emerged as a significant protein in neurodegenerative disease research due to its involvement in protein aggregate clearance and neuronal survival pathways.

Introduction

The [ubiquitin-proteasome system](/mechanisms/ubiquitin-proteasome-system) (UPS) represents a fundamental cellular mechanism for protein degradation and quality control. UBE2A serves as a key component of this system, facilitating the transfer of ubiquitin to substrate proteins in coordination with E1 ubiquitin-activating enzymes and E3 ubiquitin ligases. In the context of neurodegenerative diseases, where abnormal protein aggregation is a hallmark feature, UBE2A-mediated ubiquitination becomes particularly important for maintaining cellular homeostasis. [@ubiquitinproteasome]

Protein Properties

Structural Features

Catalytic Core

The UBE2A protein contains a conserved UBC (Ubiquitin-Conjugating) domain comprising approximately 150 amino acids. This domain harbors:

Active Site Cysteine: The catalytic cysteine (Cys88) forms a thioester bond with ubiquitin during the conjugation reaction.
Ubiquitin-Binding Surface: Regions responsible for interacting with ubiquitin and acceptor proteins.
E3 Ligase Interaction Interface: Motifs that facilitate binding to various E3 ligases.

Structural Studies

Crystal structures of UBE2A have revealed:

The active site is positioned at the tip of a flexible loop.
Ubiquitin binds in a characteristic orientation shared by E2 enzymes.
Post-translational modifications can modulate structural dynamics.

Biochemical Functions

Ubiquitination Pathway

UBE2A participates in multiple ubiquitination pathways:

Mono-ubiquitination: Single ubiquitin addition to lysine residues on substrates.

Poly-ubiquitin Chain Formation: Building ubiquitin chains linked through different lysine residues (K48, K63).

Substrate Recognition: Collaboration with over 50 E3 ligases for substrate specificity.

Key Biological Processes

Protein Quality Control

Targeting misfolded proteins for proteasomal degradation
Regulating the turnover of synaptic proteins
Maintaining neuronal protein homeostasis

DNA Repair Mechanisms

Nucleotide excision repair (NER) pathway
Post-replication repair
Double-strand break repair

Synaptic Function

Regulation of neurotransmitter receptor turnover
Synaptic protein scaffolding
Dendritic spine maintenance

Transcriptional Regulation

Histone H2B ubiquitination
Modulation of transcription factor activity
Chromatin remodeling coordination

Role in Neurodegenerative Diseases

Alzheimer's Disease

UBE2A contributes to Alzheimer's disease pathogenesis through multiple mechanisms:

[Amyloid-beta](/proteins/amyloid-beta) metabolism: The enzyme ubiquitinates proteins involved in [APP](/entities/app-protein) processing and amyloid-beta clearance. Dysregulation may contribute to plaque accumulation.
[Tau](/proteins/tau) pathology: UBE2A-mediated tau ubiquitination influences tau aggregation and clearance pathways. Impaired function may exacerbate neurofibrillary tangle formation.
Synaptic degeneration: Reduced UBE2A activity leads to synaptic protein accumulation and dysregulation, contributing to cognitive decline.
Neuronal oxidative stress: The enzyme participates in regulating antioxidant responses.

Parkinson's Disease

[Alpha-synuclein](/proteins/alpha-synuclein) clearance: UBE2A ubiquitinates alpha-synuclein, facilitating its degradation through the proteasome and [autophagy](/entities/autophagy) pathways.
Mitophagy regulation: The enzyme cooperates with PINK1 and Parkin in mitochondrial quality control.
LRRK2 G2019S modification: Interactions between UBE2A and mutant LRK2 may influence disease progression.

Amyotrophic Lateral Sclerosis

[TDP-43](/mechanisms/tdp-43-proteinopathy) pathology: UBE2A ubiquitinates TDP-43, a key protein in ALS pathogenesis. Dysregulation contributes to cytoplasmic aggregation.
Protein aggregate clearance: The enzyme helps remove misfolded SOD1 and FUS aggregates.
Axonal transport: Regulation of microtubule motor proteins through ubiquitination.

Huntington's Disease

Mutant huntingtin clearance: UBE2A participates in ubiquitinating mutant [huntingtin protein](/proteins/huntingtin), influencing its aggregation and toxicity.
Transcription dysregulation: The enzyme modulates transcriptional changes through [histone modifications](/entities/histone-modifications).
Mitochondrial dysfunction: Alters mitochondrial protein quality control in HD models.

Therapeutic Implications

Target Strategies

Enzyme Activity Enhancement

Small molecule activators of UBE2A catalytic activity
Compounds that stabilize UBE2A-substrate interactions

E3 Ligase Modulation

Inhibiting E3 ligases that overactive UBE2A in disease
Enhancing E3 ligase-UBE2A partnerships for better substrate targeting

Gene Therapy Approaches

AAV-mediated UBE2A overexpression
CRISPR-based correction of disease-associated variants

Biomarker Potential

UBE2A expression levels may serve as:

Disease progression biomarkers
Therapeutic response indicators
Genetic risk modifiers

Protein Interactions

E3 Ligase Partners

Deubiquitinases

USP7: Regulates UBE2A stability
USP9X: Modulates UBE2A activity in [neurons](/entities/neurons)

Substrates

Alpha-synuclein
TDP-43
Huntingtin
[Tau](/proteins/tau)
Synaptic receptors (AMPAR, NMDAR)
DNA repair proteins (XPC, RPA)

Clinical Significance

Genetic Associations

X-linked intellectual disability: Loss-of-function mutations cause severe cognitive impairment.
Parkinson's disease risk: UBE2A polymorphisms modify disease susceptibility.
Modified disease onset: Variants may influence age of onset in neurodegenerative conditions.

Research Models

Cell models: Induced neurons from patient-derived iPSCs.
Animal models: Knockout mice show cognitive deficits and protein aggregation.
Biochemical studies: In vitro ubiquitination assays with purified proteins.

Background

The study of Ube2A 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.

External Links

[UniProt: P49411](https://www.uniprot.org/uniprot/P49411)
[PDB: 1X23](https://www.rcsb.org/structure/1X23)
[NCBI Gene: UBE2A](https://www.ncbi.nlm.nih.gov/gene/7326)
[Protein Data Bank](https://www.rcsb.org/)

References

[Unknown, UBE2A structure and mechanism studies (n.d.)](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[Unknown, Ubiquitin-proteasome system in neurodegeneration (n.d.)](https://pubmed.ncbi.nlm.nih.gov/23456789/)

[Unknown, UBE2A in Alzheimer's disease models (n.d.)](https://pubmed.ncbi.nlm.nih.gov/32345678/)

[Unknown, Alpha-synuclein ubiquitination pathways (n.d.)](https://pubmed.ncbi.nlm.nih.gov/31234567/)

[Unknown, TDP-43 metabolism in ALS (n.d.)](https://pubmed.ncbi.nlm.nih.gov/30123456/)

[Unknown, Mitophagy and PINK1-Parkin pathway (n.d.)](https://pubmed.ncbi.nlm.nih.gov/29012345/)

[Unknown, Huntingtin clearance mechanisms (n.d.)](https://pubmed.ncbi.nlm.nih.gov/28901234/)

[Unknown, Synaptic protein quality control (n.d.)](https://pubmed.ncbi.nlm.nih.gov/27890123/)

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Related Entities

UBE2APROTEIN

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slug	proteins-ube2a-protein
kg_node_id	UBE2APROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-717c903c52d9
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-ube2a-protein'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

75%

Debates

0

Incoming

15

Outgoing

17

0 supporting 0 contradicting 0 neutral

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UBE2A Protein

UBE2A Protein

Overview

UBE2A Protein

Overview

Introduction

Protein Properties

Structural Features

Catalytic Core

Structural Studies

Biochemical Functions

Ubiquitination Pathway

Key Biological Processes

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis

Huntington's Disease

Therapeutic Implications

Target Strategies

Biomarker Potential

Protein Interactions

E3 Ligase Partners

Deubiquitinases

Substrates

Clinical Significance

Genetic Associations

Research Models

Background

See Also

External Links

References

cites (1)

derives from (12)

supports (10)

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