Structural insights into Ubr1-mediated N-degron polyubiquitination

Man Pan (), Qingyun Zheng, Tian Wang, Lujun Liang, Junxiong Mao, Chong Zuo, Ruichao Ding, Huasong Ai, Yuan Xie, Dong Si, Yuanyuan Yu (), Lei Liu () and Minglei Zhao ()
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Man Pan: The University of Chicago
Qingyun Zheng: Tsinghua University
Tian Wang: Tsinghua University
Lujun Liang: Tsinghua University
Junxiong Mao: Tsinghua University
Chong Zuo: Tsinghua University
Ruichao Ding: Tsinghua University
Huasong Ai: Tsinghua University
Yuan Xie: The University of Chicago
Dong Si: University of Washington Bothell
Yuanyuan Yu: The University of Chicago
Lei Liu: Tsinghua University
Minglei Zhao: The University of Chicago

Nature, 2021, vol. 600, issue 7888, 334-338

Abstract: Abstract The N-degron pathway targets proteins that bear a destabilizing residue at the N terminus for proteasome-dependent degradation1. In yeast, Ubr1—a single-subunit E3 ligase—is responsible for the Arg/N-degron pathway2. How Ubr1 mediates the initiation of ubiquitination and the elongation of the ubiquitin chain in a linkage-specific manner through a single E2 ubiquitin-conjugating enzyme (Ubc2) remains unknown. Here we developed chemical strategies to mimic the reaction intermediates of the first and second ubiquitin transfer steps, and determined the cryo-electron microscopy structures of Ubr1 in complex with Ubc2, ubiquitin and two N-degron peptides, representing the initiation and elongation steps of ubiquitination. Key structural elements, including a Ubc2-binding region and an acceptor ubiquitin-binding loop on Ubr1, were identified and characterized. These structures provide mechanistic insights into the initiation and elongation of ubiquitination catalysed by Ubr1.

Date: 2021
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DOI: 10.1038/s41586-021-04097-8

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