Structural basis of E2-25K/UBB+1 interaction leading to proteasome inhibition and neurotoxicity. - AlzForum Alzheimer Research Paper of the Week


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Home: Papers of the Week

Annotation

	Ko S, Kang GB, Song SM, Lee JG, Shin DY, Yun JH, Sheng Y, Cheong C, Jeon YH, Jung YK, Arrowsmith CH, Avvakumov GV, Dhe-Paganon S, Yoo YJ, Eom SH, Lee W. Structural basis of E2-25K/UBB+1 interaction leading to proteasome inhibition and neurotoxicity. J Biol Chem. 2010 Nov 12;285(46):36070-80. PubMed Abstract

	Comments on Paper and Primary News

	Comment by: Fred van Leeuwen
	Submitted 15 September 2010 \| Permalink	Posted 15 September 2010
	Time for the Ubiquitin-Proteasome System #4 Misframed ubiquitin (UBB⁺¹) accumulates in tauopathies and in polyglutamine diseases, but not in synucleinopathies. Over the last decade, much information about this endogenous proteasome inhibitor has become available; it is dose-dependently toxic and impairs hippocampal-related contextual memory. Ko et al. provide a firm structural basis for an interaction between the E2 enzyme (E2-25K), via its UBA domain, and UBB⁺¹, leading to proteasome inhibition in relation to Aβ neurotoxicity and neuronal cell death. They anticipate that their work will lead to the discovery of new approaches to the treatment of Alzheimer and Huntington diseases and related disorders. View all comments by Fred van Leeuwen

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REAGENTS/MATERIAL:
In vitro pull-down assays- Ub or UBB⁺¹ were cloned, expressed in E. coli BL21 cells and purified on glutathione-sepharose. Wild-type or mutant E2-25K was incubated with GST alone, GST-Ub or GST-UBB⁺¹ in the presence of glutathione-sepharose beads. The bound proteins were eluted by boiling in SDS-PAGE sample buffer and analyzed by Western blotting using an anti-E2-25K antibody.

Analysis of UBB⁺¹-anchored polyUb synthesis- To assay UBB⁺¹ anchoring, the ubiquitylation activities of E2-25K and its mutants were measured based on an in vitro reaction. The reaction mixtures containing wild-type or mutant E2-25K proteins wereanalyzed by Western blotting with rat polyclonal anti-UBB⁺¹ antibody.




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