Bidirectional substrate shuttling between the 26S proteasome and the Cdc48 ATPase promotes protein degradation.
Mol Cell
; 84(7): 1290-1303.e7, 2024 Apr 04.
Article
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| MEDLINE
| ID: mdl-38401542
ABSTRACT
Most eukaryotic proteins are degraded by the 26S proteasome after modification with a polyubiquitin chain. Substrates lacking unstructured segments cannot be degraded directly and require prior unfolding by the Cdc48 ATPase (p97 or VCP in mammals) in complex with its ubiquitin-binding partner Ufd1-Npl4 (UN). Here, we use purified yeast components to reconstitute Cdc48-dependent degradation of well-folded model substrates by the proteasome. We show that a minimal system consists of the 26S proteasome, the Cdc48-UN ATPase complex, the proteasome cofactor Rad23, and the Cdc48 cofactors Ubx5 and Shp1. Rad23 and Ubx5 stimulate polyubiquitin binding to the 26S proteasome and the Cdc48-UN complex, respectively, allowing these machines to compete for substrates before and after their unfolding. Shp1 stimulates protein unfolding by the Cdc48-UN complex rather than substrate recruitment. Experiments in yeast cells confirm that many proteins undergo bidirectional substrate shuttling between the 26S proteasome and Cdc48 ATPase before being degraded.
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Banco de datos:
MEDLINE
Asunto principal:
Proteínas de Saccharomyces cerevisiae
/
Complejo de la Endopetidasa Proteasomal
Idioma:
En
Año:
2024
Tipo del documento:
Article