UBE3A

UBE3A (E6-associated protein) is an E3 ubiquitin ligase whose loss causes Angelman syndrome and whose silencing in neurons is the classic human example of genomic imprinting.

Function

UBE3A tags substrate proteins with ubiquitin for proteasomal destruction. Its best-characterized substrate relationship runs in reverse: HPV E6 protein recruits UBE3A to p53, and the ligase ubiquitinates p53 for degradation — the mechanism by which HPV-positive tumors delete their p53 response without mutating the gene. UBE3A’s normal neuronal substrates include synaptic proteins, and its dosage in the brain shapes synaptic development.

Genomic imprinting

In most tissues both parental copies of UBE3A are active. In neurons the maternal copy