Structural basis of K11/K48-branched ubiquitin chain recognition by the human 26S proteasome

2025/10/15 by Piotr Drączkowski, Szu-Ni Chen, Ting Chen +10 · 1 voice · 6 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Ubiquitin and proteasome pathways #RNA modifications and cancer #Peptidase Inhibition and Analysis

paper · doi:10.1038/s41467-025-64719-x

Abstract

Beyond the canonical K48-linked homotypic polyubiquitination for proteasome-targeted proteolysis, K11/K48-branched ubiquitin (Ub) chains are involved in fast-tracking protein turnover during cell cycle progression and proteotoxic stress. Here, we report cryo-EM structures of human 26S proteasome in a complex with a K11/K48-branched Ub chain. The structures revealed a multivalent substrate recognition mechanism involving a hitherto unknown K11-linked Ub binding site at the groove formed by RPN2 and RPN10 in addition to the canonical K48-linkage binding site formed by RPN10 and RPT4/5 coiled-coil. Additionally, RPN2 recognizes an alternating K11-K48-linkage through a conserved motif similar to the K48-specific T1 binding site of RPN1. The insights gleaned from these structures explain the molecular mechanism underlying the recognition of the K11/K48-branched Ub as a priority signal in the ubiquitin-mediated proteasomal degradation.

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Discussions

• If you're curious about how cells quickly eliminate misfolded proteins produced under proteotoxic stress or mitotic substrate during cell cycle progression, check out our latest article in Nature Comm [bsky, 16 points, 4 comments]

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