Structural basis of E2-25K/UBB+1 interaction leading to proteasome inhibition and neurotoxicity.
E2-25K/Hip2 is an unusual ubiquitin-conjugating enzyme that interacts with the frameshift mutant of ubiquitin B (UBB(+1)) and has been identified as a crucial factor regulating amyloid-β neurotoxicity. To study the structural basis of the neurotoxicity mediated by the E2-25K-UBB(+1) interaction, we determined the three-dimensional structures of UBB(+1), E2-25K and the ... E2-25K/ubiquitin, and E2-25K/UBB(+1) complex. The structures revealed that ubiquitin or UBB(+1) is bound to E2-25K via the enzyme MGF motif and residues in α9 of the enzyme. Polyubiquitylation assays together with analyses of various E2-25K mutants showed that disrupting UBB(+1) binding markedly diminishes synthesis of neurotoxic UBB(+1)-anchored polyubiquitin. These results suggest that the interaction between E2-25K and UBB(+1) is critical for the synthesis and accumulation of UBB(+1)-anchored polyubiquitin, which results in proteasomal inhibition and neuronal cell death.
Mesh Terms:
Amino Acid Sequence, Animals, Binding Sites, Cell Line, Tumor, Cell Survival, Crystallography, X-Ray, Green Fluorescent Proteins, HEK293 Cells, Humans, Hydrogen Bonding, Magnetic Resonance Spectroscopy, Microscopy, Fluorescence, Models, Molecular, Molecular Sequence Data, Multiprotein Complexes, Mutation, Proteasome Endopeptidase Complex, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, Recombinant Fusion Proteins, Sequence Homology, Amino Acid, Ubiquitin, Ubiquitin-Conjugating Enzymes
Amino Acid Sequence, Animals, Binding Sites, Cell Line, Tumor, Cell Survival, Crystallography, X-Ray, Green Fluorescent Proteins, HEK293 Cells, Humans, Hydrogen Bonding, Magnetic Resonance Spectroscopy, Microscopy, Fluorescence, Models, Molecular, Molecular Sequence Data, Multiprotein Complexes, Mutation, Proteasome Endopeptidase Complex, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, Recombinant Fusion Proteins, Sequence Homology, Amino Acid, Ubiquitin, Ubiquitin-Conjugating Enzymes
J. Biol. Chem.
Date: Nov. 12, 2010
PubMed ID: 20826778
View in: Pubmed Google Scholar
Download Curated Data For This Publication
135568
Switch View:
- Interactions 1