Allosteric control of Ubp6 and the proteasome via a bidirectional switch

Ka Ying Sharon Hung, Sven Klumpe, Markus R. Eisele, Suzanne Elsasser, Geng Tian, Shuangwu Sun, Jamie A. Moroco, Tat Cheung Cheng, Tapan Joshi, Timo Seibel, Duco Dalen, Xin-Hua Feng, Ying Lu, Huib Ovaa, John R. Engen, Byung-Hoon Lee (), Till Rudack (), Eri Sakata () and Daniel Finley ()
Additional contact information
Ka Ying Sharon Hung: Harvard Medical School
Sven Klumpe: Max Planck Institute of Biochemistry
Markus R. Eisele: Max Planck Institute of Biochemistry
Suzanne Elsasser: Harvard Medical School
Geng Tian: Harvard Medical School
Shuangwu Sun: Harvard Medical School
Jamie A. Moroco: Northeastern University
Tat Cheung Cheng: Max Planck Institute of Biochemistry
Tapan Joshi: Max Planck Institute of Biochemistry
Timo Seibel: Harvard Medical School
Duco Dalen: Leiden University Medical Center
Xin-Hua Feng: Zhejiang University
Ying Lu: Harvard Medical School
Huib Ovaa: Leiden University Medical Center
John R. Engen: Northeastern University
Byung-Hoon Lee: Daegu Gyeongbuk Institute of Science and Technology (DGIST)
Till Rudack: Ruhr University Bochum
Eri Sakata: Max Planck Institute of Biochemistry
Daniel Finley: Harvard Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-28186-y

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