UBE3A

Ubiquitin-protein ligase E3A (UBE3A) also known as E6AP ubiquitin-protein ligase (E6AP) is an enzyme that in humans is encoded by the UBE3A gene. This enzyme is involved in targeting proteins for degradation within cells.

Collision model of UBE3A

UBE3A
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4GIZ, 1C4Z, 1D5F, 1EQX, 2KR1
Identifiers
Aliases	UBE3A, ANCR, AS, E6-AP, EPVE6AP, HPVE6A, ubiquitin protein ligase E3A, PIX1
External IDs	OMIM: 601623; MGI: 105098; HomoloGene: 7988; GeneCards: UBE3A; OMA:UBE3A - orthologs
Gene location (Human) Chr. Chromosome 15 (human)[1] Band 15q11.2 Start 25,333,728 bp[1] End 25,439,051 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7 B5|7 33.95 cM Start 59,228,750 bp[2] End 59,311,536 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in sperm Skeletal muscle tissue of rectus abdominis Achilles tendon Skeletal muscle tissue of biceps brachii mucosa of paranasal sinus nipple Epithelium of choroid plexus vastus lateralis muscle pylorus cardia Top expressed in Rostral migratory stream vas deferens pineal gland ventromedial nucleus medial ganglionic eminence arcuate nucleus efferent ductule median eminence paraventricular nucleus of hypothalamus lateral septal nucleus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function metal ion binding transcription coactivator activity ubiquitin-protein transferase activity protein binding ubiquitin protein ligase activity transferase activity Cellular component cytosol proteasome complex nucleus cytoplasm Biological process ubiquitin-dependent protein catabolic process prostate gland growth rhythmic process proteolysis positive regulation of phosphatidylinositol 3-kinase signaling protein K48-linked ubiquitination viral process brain development regulation of ubiquitin-dependent protein catabolic process ovarian follicle development sperm entry protein ubiquitination positive regulation of protein ubiquitination positive regulation of transcription by RNA polymerase II protein autoubiquitination regulation of circadian rhythm androgen receptor signaling pathway response to progesterone progesterone receptor signaling pathway protein polyubiquitination proteasome-mediated ubiquitin-dependent protein catabolic process response to cocaine response to hydrogen peroxide negative regulation of dendritic spine morphogenesis cellular response to brain-derived neurotrophic factor stimulus Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 7337 22215 Ensembl ENSG00000114062 ENSMUSG00000025326 UniProt Q05086 O08759 RefSeq (mRNA) NM_000462 NM_130838 NM_130839 NM_001354505 NM_001354506 NM_001354509 NM_001354512 NM_001354523 NM_001354526 NM_001354540 NM_001354541 NM_001354543 NM_001354545 NM_001354547 NM_001354549 NM_001354550 NM_001354507 NM_001354508 NM_001354511 NM_001354513 NM_001354538 NM_001354539 NM_001354542 NM_001354544 NM_001354546 NM_001354548 NM_001354551 NM_001374461 NM_001033962 NM_011668 NM_173010 RefSeq (protein) NP_000453 NP_570853 NP_570854 NP_001341434 NP_001341435 NP_001341438 NP_001341441 NP_001341452 NP_001341455 NP_001341469 NP_001341470 NP_001341472 NP_001341474 NP_001341476 NP_001341478 NP_001341479 NP_001341436 NP_001341437 NP_001341440 NP_001341442 NP_001341467 NP_001341468 NP_001341471 NP_001341473 NP_001341475 NP_001341477 NP_001341480 NP_001361390 NP_001029134 NP_035798 NP_001380595 NP_001380597 NP_001380598 NP_001380599 NP_001380600 NP_001380601 NP_766598 NP_001380902 Location (UCSC) Chr 15: 25.33 – 25.44 Mb Chr 7: 59.23 – 59.31 Mb PubMed search [3] [4]
Wikidata
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Gene

The UBE3A gene is located on the long (q) arm of chromosome 15 between positions 11 and 13, from base pair 23,133,488 to base pair 23,235,220.

Silencing of Ube3a on the paternal allele is thought to occur through the Ube3a-ATS part of a lincRNA called "LNCAT"^[5] (Large Non-Coding Antisense Transcript).

Tissue distribution

Both copies of the UBE3A gene are active in most of the body's tissues. In most neurons, however, only the copy inherited from a person's mother (the maternal copy) is normally active; this is known as paternal imprinting. Recent evidence shows that at least some glial cells and neurons may exhibit biallelic expression of UBE3A.^[6][7] Further work is thus needed to delineate a complete map of UBE3A imprinting in humans and model organisms such as mice.

Function

The UBE3A gene encodes ubiquitin protein ligase E3A (also known as E6AP), a multifunctional enzyme that plays a crucial role in cellular protein homeostasis and neural development. Its primary function is to act as an E3 ubiquitin ligase, attaching ubiquitin molecules to specific substrate proteins, thereby marking them for degradation by the proteasome system.^[8][9] This process is essential for removing damaged or unnecessary proteins, maintaining cellular health, and regulating the balance of protein synthesis and degradation (proteostasis) at synapses, which is vital for synaptic plasticity, learning, and memory.^[8][10] In addition to its ligase activity, UBE3A also serves as a transcriptional co-activator, influencing the expression of genes involved in hormone signaling and neural function.^[9] Notably, in neurons, only the maternal copy of the UBE3A gene is typically active due to genomic imprinting, and disruptions in its expression are linked to neurodevelopmental disorders such as Angelman syndrome and autism spectrum disorders.^[9] UBE3A's precise regulation is therefore critical for normal brain development and function, as both loss and overexpression can lead to significant neurological and behavioral abnormalities.^[10]

Clinical significance

Mutations within the UBE3A gene are responsible for some cases of Angelman syndrome and Prader-Willi syndrome. Most of these mutations result in an abnormally short, nonfunctional version of ubiquitin protein ligase E3A. Because the copy of the gene inherited from a person's father (the paternal copy) is normally inactive in the brain, a mutation in the remaining maternal copy prevents any of the enzyme from being produced in the brain. This loss of enzyme function likely causes the characteristic features of these two conditions.^{[citation needed]}

The UBE3A gene lies within the human chromosomal region 15q11-13. Other abnormalities in this region of chromosome 15 can also cause Angelman syndrome. These chromosomal changes include deletions, rearrangements (translocations) of genetic material, and other abnormalities. Like mutations within the gene, these chromosomal changes prevent any functional ubiquitin protein ligase E3A from being produced in the brain.

UBE3A associates with the E6 protein of certain strains of HPV. This interaction promotes the polyubiquitination and subsequent degradation of the tumor suppressor gene p53, thereby enabling the immortalization of infected cells.^[11] Strains of HPV with this ability have a higher risk of causing HPV-associated cancers. UBE3A is also known as E6AP or E6-associated protein in reference to this mechanism.

Interactions

UBE3A has been shown to interact with:

• BLK,^[12]
• Lck,^[12]
• MCM7,^[13]
• MECP2,^[14]
• Progesterone receptor,^[15]
• TSC2,^[16][17]
• UBE2D1,^[18][19]
• UBE2D2,^[20][21]
• UBE2L3,^[18][20][22]
• UBQLN1,^[23] and
• UBQLN2.^[23]