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  Allosteric control of Ubp6 and the proteasome via a bidirectional switch

Hung, K. Y. S., Klumpe, S., Eisele, M. R., Elsasser, S., Tian, G., Sun, S., et al. (2022). Allosteric control of Ubp6 and the proteasome via a bidirectional switch. Nature Communications, 13(1): 838. doi:10.1038/s41467-022-28186-y.

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 Creators:
Hung, Ka Ying Sharon1, Author
Klumpe, Sven2, Author              
Eisele, Markus R.2, Author              
Elsasser, Suzanne1, Author
Tian, Geng1, Author
Sun, Shuangwu1, Author
Moroco, Jamie A.1, Author
Cheng, Tat Cheung2, Author
Joshi, Tapan2, Author
Seibel, Timo1, Author
Van Dalen, Duco1, Author
Feng, Xin-Hua1, Author
Lu, Ying1, Author
Ovaa, Huib1, Author
Engen, John R.1, Author
Lee, Byung-Hoon1, Author
Rudack, Till1, Author
Sakata, Eri2, Author              
Finley, Daniel1, Author
Affiliations:
1external, ou_persistent22              
2Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565142              

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Free keywords: HUMAN 26S PROTEASOME; DEUBIQUITINATING ENZYME; STRUCTURAL INSIGHTS; CONFORMATIONAL LANDSCAPE; REVEALS MECHANISMS; CRYSTAL-STRUCTURE; PROTEINS; DEGRADATION; USP14; ASSOCIATIONScience & Technology - Other Topics;
 Abstract: The interplay of the proteasome and deubiquitinase Ubp6 is crucial for the degradation of ubiquitylated substrates. Here, the authors provide structural insights into the allosteric mechanism by which the activities of both Ubp6 and the proteasome are regulated. The proteasome recognizes ubiquitinated proteins and can also edit ubiquitin marks, allowing substrates to be rejected based on ubiquitin chain topology. In yeast, editing is mediated by deubiquitinating enzyme Ubp6. The proteasome activates Ubp6, whereas Ubp6 inhibits the proteasome through deubiquitination and a noncatalytic effect. Here, we report cryo-EM structures of the proteasome bound to Ubp6, based on which we identify mutants in Ubp6 and proteasome subunit Rpt1 that abrogate Ubp6 activation. The Ubp6 mutations define a conserved region that we term the ILR element. The ILR is found within the BL1 loop, which obstructs the catalytic groove in free Ubp6. Rpt1-ILR interaction opens the groove by rearranging not only BL1 but also a previously undescribed network of three interconnected active-site-blocking loops. Ubp6 activation and noncatalytic proteasome inhibition are linked in that they are eliminated by the same mutations. Ubp6 and ubiquitin together drive proteasomes into a unique conformation associated with proteasome inhibition. Thus, a multicomponent allosteric switch exerts simultaneous control over both Ubp6 and the proteasome.

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Language(s): eng - English
 Dates: 2022
 Publication Status: Published online
 Pages: 13
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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 13 (1) Sequence Number: 838 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723