E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and transfers it to its substrates. Several substrates have been identified including the ARNTL/BMAL1, ARC, RAD23A and RAD23B, MCM7 (which is involved in DNA replication), annexin A1, the PML tumor suppressor, and the cell cycle regulator CDKN1B (PubMed:20211139, PubMed:24728990). Additionally, may function as a cellular quality control ubiquitin ligase by helping the degradation of the cytoplasmic misfolded proteins. Finally, UBE3A also promotes its own degradation in vivo (By similarity). Plays an important role in the regulation of the circadian clock: involved in the ubiquitination of the core clock component ARNTL/BMAL1, leading to its proteasomal degradation (PubMed:24728990). Acts as a regulator of synaptic development by mediating ubiquitination and degradation of ARC (PubMed:20211139). Synergizes with WBP2 in enhancing PGR activity (By similarity). S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine. Protein modification; protein ubiquitination. The active form is probably a homotrimer. Binds UBQLN1 and UBQLN2. Interacts with the 26S proteasome. Interacts with BPY2. Interacts with HIF1AN, MAPK6 AND NEURL4; interaction with MAPK6 may be mediated by NEURL4. Interacts with the proteasomal subunit PSMD4. Interacts with ARNTL/BMAL1 (PubMed:24728990). Interacts with ARC (PubMed:20211139). Interacts with ESR1 and WBP2 (By similarity). Widely expressed. Most abundant in brain, heart and thymus. Up-regulated in response to neuronal activity. Phosphorylation at Tyr-654 by ABL1 impairs E3 ligase activity. Mice with maternal deficiency display autism spectrum disorders, characterized by motor dysfunction, inducible seizures and a context-dependent learning deficit (PubMed:9808466, PubMed:11895368). Long-term potentiation (LTP) is severely impaired despite normal baseline synaptic transmission and neuroanatomy (PubMed:9808466). The cytoplasmic abundance of p53/TP53 is increased in postmitotic neurons (PubMed:9808466). Accumulation of ARC protein in neurons, resulting in the excessive internalization of AMPA receptors (AMPARs) at synapses and impaired synaptic function (PubMed:20211139). The Ube3a locus is imprinted with silencing of the paternal allele in hippocampus and cerebellum in mice. A cysteine residue is required for ubiquitin-thioester formation.