Structural insights into Ubr1-mediated N-degron polyubiquitination

Article

关键词: END RULE PATHWAY;    UBIQUITIN-LIGASE;    ADAPTER PROTEIN;    COHESIN SUBUNIT;    E3 LIGASE;    SUBSTRATE;    RECOGNITION;    DEGRADATION;    ACTIVATION;    MECHANISM;   

DOI  :  10.1038/s41586-021-04097-8

来源: SCIE

【 摘 要 】

The N-degron pathway targets proteins that bear a destabilizing residue at the N terminus for proteasome-dependent degradation(1). In yeast, Ubr1-a single-subunit E3 ligase-is responsible for the Arg/N-degron pathway(2). 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.

【 授权许可】

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