E2-25K/Hip2 is an unusual ubiquitin-conjugating enzyme that interacts with the frameshift mutant of ubiquitinB(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.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology