6k2k | pdb_00006k2k
Solution structure of MUL1-RING domain
Structural highlights
FunctionMUL1_HUMAN Exhibits weak E3 ubiquitin-protein ligase activity (PubMed:18591963, PubMed:19407830, PubMed:22410793). 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 (PubMed:18591963, PubMed:19407830, PubMed:22410793). Can ubiquitinate AKT1 preferentially at 'Lys-284' involving 'Lys-48'-linked polyubiquitination and seems to be involved in regulation of Akt signaling by targeting phosphorylated Akt to proteosomal degradation (PubMed:22410793). Proposed to preferentially act as a SUMO E3 ligase at physiological concentrations (PubMed:19407830). Plays a role in the control of mitochondrial morphology by promoting mitochondrial fragmentation, and influences mitochondrial localization (PubMed:19407830, PubMed:18207745, PubMed:18213395). Likely to promote mitochondrial fission through negatively regulating the mitochondrial fusion proteins MFN1 and MFN2, acting in a pathway that is parallel to the PRKN/PINK1 regulatory pathway (PubMed:24898855). May also be involved in the sumoylation of the membrane fission protein DNM1L (PubMed:18207745, PubMed:19407830). Inhibits cell growth (PubMed:18591963, PubMed:22410793). When overexpressed, activates JNK through MAP3K7/TAK1 and induces caspase-dependent apoptosis (PubMed:23399697). Involved in the modulation of innate immune defense against viruses by inhibiting DDX58-dependent antiviral response (PubMed:23399697). Can mediate DDX58 sumoylation and disrupt its polyubiquitination (PubMed:23399697).[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedMitochondrial E3 ubiquitin ligase 1 (MUL1) is a multifunctional mitochondrial protein involved in various biological processes such as mitochondrial dynamics, cell growth, apoptosis, and mitophagy. MUL1 mediates the ubiquitylation of mitochondrial p53 for proteasomal degradation. Although the interaction of MUL1-RING domain with its substrate, p53, is a unique mechanism in RING-mediated ubiquitylation, the molecular basis of this process remains unknown. In this study, we determined the solution structure of the MUL1-RING domain and characterized its interaction with the p53 transactivation domain (p53-TAD) by nuclear magnetic resonance (NMR) spectroscopy. The overall structure of the MUL1-RING domain is similar to those of RING domains of other E3 ubiquitinases. The MUL1-RING domain adopts a betabetaalphabeta fold with three anti-parallel beta-strands and one alpha-helix, containing a canonical cross-brace motif for the ligation of two zinc ions. Through NMR chemical shift perturbation experiments, we determined the p53-TAD-binding site in the MUL1-RING domain and showed that the MUL1-RING domain interacts mainly with the p53-TAD2 subdomain composed of residues 39-57. Taken together, our results provide a molecular basis for the novel recognition mechanism of the p53-TAD substrate by the MUL1-RING domain. Solution structure of MUL1-RING domain and its interaction with p53 transactivation domain.,Lee MS, Lee SO, Lee MK, Yi GS, Lee CK, Ryu KS, Chi SW Biochem Biophys Res Commun. 2019 Jun 21. pii: S0006-291X(19)31237-9. doi:, 10.1016/j.bbrc.2019.06.101. PMID:31235254[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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