Structural basis of E2-25K/UBB+1 interaction leading to proteasome inhibition and neurotoxicity

Sunggeon Ko, Gil Bu Kang, Sung Min Song, Jung Gyu Lee, Dong Yeon Shin, Ji Hye Yun, Yi Sheng, Chaejoon Cheong, Young Ho Jeon, Yong Keun Jung, Cheryl H. Arrowsmith, George V. Avvakumov, Sirano Dhe-Paganon, Yung Joon Yoo, Soo Hyun Eom, Weontae Lee

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)36070-36080
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number46
DOIs
Publication statusPublished - 2010 Nov 12

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Structural basis of E2-25K/UBB<sup>+1</sup> interaction leading to proteasome inhibition and neurotoxicity'. Together they form a unique fingerprint.

  • Cite this

    Ko, S., Kang, G. B., Song, S. M., Lee, J. G., Shin, D. Y., Yun, J. H., Sheng, Y., Cheong, C., Jeon, Y. H., Jung, Y. K., Arrowsmith, C. H., Avvakumov, G. V., Dhe-Paganon, S., Yoo, Y. J., Eom, S. H., & Lee, W. (2010). Structural basis of E2-25K/UBB+1 interaction leading to proteasome inhibition and neurotoxicity. Journal of Biological Chemistry, 285(46), 36070-36080. https://doi.org/10.1074/jbc.M110.145219