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FUNCTION 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 (PubMed:10373495, PubMed:16772533, PubMed:19204938, PubMed:19233847, PubMed:19325566, PubMed:19591933, PubMed:22645313, PubMed:24273172, PubMed:24728990, PubMed:30020076). Several substrates have been identified including the BMAL1, ARC, LAMTOR1, RAD23A and RAD23B, MCM7 (which is involved in DNA replication), annexin A1, the PML tumor suppressor, and the cell cycle regulator CDKN1B (PubMed:10373495, PubMed:19204938, PubMed:19325566, PubMed:19591933, PubMed:22645313, PubMed:24728990, PubMed:30020076). Additionally, may function as a cellular quality control ubiquitin ligase by helping the degradation of the cytoplasmic misfolded proteins (PubMed:19233847). Finally, UBE3A also promotes its own degradation in vivo. Plays an important role in the regulation of the circadian clock: involved in the ubiquitination of the core clock component BMAL1, leading to its proteasomal degradation (PubMed:24728990). Acts as transcriptional coactivator of progesterone receptor PGR upon progesterone hormone activation (PubMed:16772533). Acts as a regulator of synaptic development by mediating ubiquitination and degradation of ARC (By similarity). Required for synaptic remodeling in neurons by mediating ubiquitination and degradation of LAMTOR1, thereby limiting mTORC1 signaling and activity-dependent synaptic remodeling (By similarity). Synergizes with WBP2 in enhancing PGR activity (PubMed:16772533).FUNCTION (Microbial infection) Catalyzes the high-risk human papilloma virus E6-mediated ubiquitination of p53/TP53, contributing to the neoplastic progression of cells infected by these viruses.CATALYTIC ACTIVITY 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.PATHWAY Protein modification; protein ubiquitination.SUBUNIT 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 ESR1 and WBP2 (PubMed:16772533, PubMed:21642474). Interacts with BMAL1 (PubMed:24728990). Interacts with ARC (By similarity).SUBUNIT (Microbial infection) Interacts with HCV core protein and targets it to degradation.SUBUNIT (Microbial infection) Interacts with the E6 protein of the cancer-associated human papillomavirus types 16 and 18. The E6/E6-AP complex binds to and targets the p53/TP53 tumor-suppressor protein for ubiquitin-mediated proteolysis.INTERACTION Phosphorylation at Tyr-659 by ABL1 impairs E3 ligase activity and protects p53/TP53 from degradation in (HPV)-infected cells.DISEASE The disease is caused by variants affecting the gene represented in this entry.MISCELLANEOUS A cysteine residue is required for ubiquitin-thioester formation.
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