8v0e
ANK repeat of MIB1
Structural highlights
DiseaseMIB1_HUMAN Left ventricular noncompaction. The disease is caused by mutations affecting the gene represented in this entry. FunctionMIB1_HUMAN E3 ubiquitin-protein ligase that mediates ubiquitination of Delta receptors, which act as ligands of Notch proteins. Positively regulates the Delta-mediated Notch signaling by ubiquitinating the intracellular domain of Delta, leading to endocytosis of Delta receptors. Probably mediates ubiquitination and subsequent proteasomal degradation of DAPK1, thereby antagonizing anti-apoptotic effects of DAPK1 to promote TNF-induced apoptosis (By similarity). Involved in ubiquitination of centriolar satellite CEP131, CEP290 and PCM1 proteins and hence inhibits primary cilium formation in proliferating cells. Mediates 'Lys-63'-linked polyubiquitination of TBK1, which probably participates in kinase activation.[1] Publication Abstract from PubMedMind bomb 1 (MIB1) is a RING E3 ligase that ubiquitinates Notch ligands, a necessary step for induction of Notch signaling. The structural basis for binding of the JAG1 ligand by the N-terminal region of MIB1 is known, yet how the ankyrin (ANK) and RING domains of MIB1 cooperate to catalyze ubiquitin transfer from E2 approximately Ub to Notch ligands remains unclear. Here, we show that the third RING domain and adjacent coiled coil region (ccRING3) drive MIB1 dimerization and that MIB1 ubiquitin transfer activity relies solely on ccRING3. We report X-ray crystal structures of a UbcH5B-ccRING3 complex and the ANK domain. Directly tethering the MIB1 N-terminal region to ccRING3 forms a minimal MIB1 protein sufficient to induce a Notch response in receiver cells and rescue mib knockout phenotypes in flies. Together, these studies define the functional elements of an E3 ligase needed for ligands to induce a Notch signaling response. Structural requirements for activity of Mind bomb1 in Notch signaling.,Cao R, Gozlan O, Airich A, Tveriakhina L, Zhou H, Jiang H, Cole PA, Aster JC, Klein T, Sprinzak D, Blacklow SC Structure. 2024 Jul 26:S0969-2126(24)00274-0. doi: 10.1016/j.str.2024.07.011. PMID:39121852[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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