E3 ubiquitin-protein ligase that promotes 'Lys-48'-linked ubiquitination of target proteins, leading to their proteasomal degradation (PubMed:15673284). Promotes ubiquitination of DIO2, leading to its degradation (PubMed:19651899). Promotes ubiquitination of SQLE, leading to its degradation (PubMed:24449766). E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates. May cooperate with UBE2G1 (PubMed:15673284). 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. Interacts with DIO2 (PubMed:19651899). Interacts with SQLE (PubMed:24449766). Present in brain (at protein level). The RING-CH-type zinc finger domain is required for E3 ligase activity. Auto-ubiquitinated, which results in proteasomal degradation. The disease is caused by variants affecting the gene represented in this entry. Truncated N-terminus. Extended N-terminus.