Structural basis of K11/K48-branched ubiquitin chain recognition by the human 26S proteasome.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41093839.
- Also identified by DOI 10.1038/s41467-025-64719-x and PMC identifier 12528685.
- Licence recorded as CC BY-NC-ND.
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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.
Medical subject headings
- Proteasome Endopeptidase Complex
- Ubiquitin