UBE2A Human
Description
Introduction to UBE2A Human
UBE2A (Ubiquitin-Conjugating Enzyme E2 A) is a critical component of the ubiquitin-proteasome system (UPS), encoded by the UBE2A gene located on the X chromosome (Xq24) . It functions as an E2 enzyme, facilitating the covalent attachment of ubiquitin to substrate proteins, targeting them for degradation or functional modification. This process is essential for cellular homeostasis, DNA repair, and protein quality control .
Gene Structure and Isoforms
The UBE2A gene spans ~15 kb and contains six exons, producing multiple alternatively spliced isoforms. The canonical transcript (NM_003336.2) encodes a 152-amino acid protein with a conserved ubiquitin-conjugating (UBCc) catalytic domain . Key isoforms include:
| Feature | Description |
|---|---|
| Chromosomal Location | Xq24 |
| Domain Structure | UBCc domain (aa 1–150) critical for ubiquitin transfer |
| Splice Variants | Multiple isoforms with tissue-specific expression |
Functional Roles in Cellular Processes
UBE2A participates in diverse pathways:
DNA Repair and Genome Stability
UBE2A interacts with RAD18 to mediate post-replicative DNA damage repair, ensuring genomic integrity .
Mechanotransduction and Cell Signaling
UBE2A/B shuttles between the nucleus and cytoplasm in response to mechanical stress, regulating YAP/TAZ-independent pathways and chromatin remodeling via histone ubiquitination .
Neurological and Developmental Functions
UBE2A is enriched in brain regions (e.g., hippocampus, neocortex) and is implicated in learning and memory. Its dysregulation correlates with Alzheimer’s disease and neurodegenerative disorders .
Clinical Relevance and Genetic Disorders
Mutations in UBE2A are associated with severe phenotypes, particularly in males due to X-linked inheritance:
X-Linked Intellectual Disability (XLID) Type Nascimento
Characterized by:
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Moderate to severe intellectual disability
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Speech impairment
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Dysmorphic features (e.g., synophrys, depressed nasal bridge)
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Urogenital anomalies (e.g., micropenis)
Neurodegenerative Diseases
UBE2A deficiency correlates with:
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Alzheimer’s disease: Reduced UBE2A levels in neocortex and hippocampus disrupt amyloid clearance .
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Parkinson’s disease: Impaired ubiquitination exacerbates protein aggregation .
Oncology
UBE2A mutations are recurrently acquired in chronic myeloid leukemia (CML) blast crisis, modulating CSF3R and ITGB4 expression to drive leukemogenesis .
Experimental Models
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Ube2a−/y mice: Show impaired hippocampal learning but no overt motor deficits, highlighting species-specific phenotypes .
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Cellular assays: UBE2A/B mediates mechanotransduction via histone H2B ubiquitination, regulating chromatin accessibility .
Diagnostic and Therapeutic Implications
Product Specs
MGSSHHHHHH SSGLVPRGSH MSTPARRRLM RDFKRLQEDP PAGVSGAPSE NNIMVWNAVI FGPEGTPFED GTFKLTIEFT EEYPNKPPTV RFVSKMFHPN VYADGSICLD ILQNRWSPTY DVSSILTSIQ SLLDEPNPNS PANSQAAQLY QENKREYEKR VSAIVEQSWR DC.
Q&A
What is the primary biological role of UBE2A in human cells?
UBE2A facilitates ubiquitination, a post-translational modification process critical for protein degradation, DNA repair, and synaptic plasticity. Its enzymatic activity involves transferring ubiquitin to substrate proteins, targeting them for proteasomal degradation or functional modulation. Unlike its homolog UBE2B, UBE2A shows tissue-specific expression patterns, with heightened activity in neural progenitors during corticogenesis . Experimental validation typically involves:
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Knockout/overexpression models: CRISPR-Cas9-mediated editing in iPSCs to assess morphological changes (e.g., nuclei enlargement) .
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Ubiquitination assays: Immunoprecipitation followed by western blotting to identify substrate specificity .
Which genetic disorders are associated with UBE2A mutations?
UBE2A mutations cause X-linked intellectual disability type Nascimento (XIDTN), characterized by:
Diagnostic workflows combine exome sequencing (e.g., Illumina NovaSeq 6000) with functional validation via RT-PCR to detect aberrant splicing variants .
What are common experimental models for studying UBE2A dysfunction?
iPSC-derived neural models are preferred for modeling neurodevelopmental defects:
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Reprogramming: Peripheral blood mononuclear cells (PBMCs) or fibroblasts are transduced with Yamanaka factors (OCT4, SOX2, KLF4, c-MYC) .
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Differentiation: Neural induction via dual SMAD inhibition (LDN193189 + SB431542) .
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Phenotyping: Electrophysiological assays (patch-clamp) and calcium imaging to assess neuronal activity .
Animal models: While UBE2A knockout mice exhibit female sterility, they lack overt neurocognitive deficits, highlighting species-specific functional divergence .
How can researchers resolve contradictions between in vitro and clinical data in UBE2A studies?
Discrepancies often arise from:
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Genetic modifiers: Unaccounted epistatic interactions in patient genomes versus isogenic iPSC lines .
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Temporal expression: Transient UBE2A overexpression may not recapitulate developmental-stage-specific roles .
Methodological solutions:
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Isogenic controls: Use CRISPR-Cas9 to generate patient-derived iPSCs with corrected mutations .
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Multi-omics integration: Combine transcriptomics (RNA-seq), proteomics (LC-MS/MS), and epigenomics (ATAC-seq) to identify compensatory pathways .
What strategies improve detection of UBE2A splice variants in clinical cohorts?
Novel splice-site mutations (e.g., c.331-2A>G) require:
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In silico prediction: Tools like SpliceAI or MaxEntScan to assess splice site disruption .
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Experimental validation:
Case study: A Chinese patient with c.331-2A>G showed a frameshift transcript (p.L112SfsX17) via agarose gel electrophoresis and Sanger sequencing .
How do researchers address the functional redundancy between UBE2A and UBE2B?
Despite 96% sequence homology, UBE2A and UBE2B show non-overlapping roles:
| Parameter | UBE2A | UBE2B |
|---|---|---|
| Subcellular localization | Nuclear-cytoplasmic shuttle | Predominantly cytoplasmic |
| Knockout phenotype | Intellectual disability | Male infertility |
Experimental approaches:
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Co-immunoprecipitation: Identify unique binding partners (e.g., UBE2A interacts with HUWE1 E3 ligase) .
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CRISPR interference: Dual knockdown in iPSC-derived neurons to assess synergistic effects .
What biomarkers are emerging for UBE2A-related therapeutic trials?
Functional biomarkers:
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fNIRS (functional Near Infrared Spectroscopy): Measures prefrontal cortex activation during cognitive tasks (sensitivity: 82%) .
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Electroretinography: Detects retinal dysfunction in 40% of patients, correlating with CNS defects .
Molecular biomarkers:
Product Science Overview
Ubiquitin Conjugating Enzyme E2A, also known as UBE2A, is a crucial component of the ubiquitination pathway, which is essential for regulating protein degradation and maintaining cellular homeostasis. UBE2A is a human recombinant enzyme that plays a pivotal role in the second step of the ubiquitination process, where it acts as a ubiquitin carrier, transferring ubiquitin from the E1 activating enzyme to the E3 ligase enzyme .
UBE2A is characterized by its highly conserved ubiquitin-conjugating (UBC) domain, which is responsible for its enzymatic activity. The enzyme’s structure allows it to interact with both the E1 activating enzyme and the E3 ligase, facilitating the transfer of ubiquitin to target proteins. This process is critical for tagging proteins for degradation via the proteasome, thereby regulating various cellular processes such as cell cycle progression, DNA repair, and response to stress .
The ubiquitination pathway, in which UBE2A is a central player, is vital for controlling protein turnover and quality control within cells. Dysregulation of this pathway can lead to various diseases, including cancer, neurodegenerative disorders, and immune system dysfunctions. UBE2A, in particular, has been implicated in several pathophysiological conditions due to its role in protein degradation and cellular regulation .
Recent studies have explored the potential of UBE2A in targeted protein degradation strategies. For instance, chimeric human E2 ubiquitin-conjugating enzymes have been engineered to direct specific proteins to the ubiquitination machinery, enhancing their degradation. This approach, known as Proteolysis-Targeting Chimeras (PROTACs), leverages the natural role of UBE2A in the ubiquitin-proteasome system to selectively degrade target proteins, offering promising therapeutic avenues for diseases characterized by aberrant protein accumulation .
