Structures of the 26S proteasome in complex with the Hsp70 co-chaperone Bag1 reveal a mechanism for direct substrate transfer.

Coupling between the chaperone and degradation systems, particularly under stress, is essential for eliminating unfolded proteins. The co-chaperone Bag1 links Hsp70 to the 26S proteasome, recruiting Hsp70-bound clients for proteasomal degradation. Here, we present cryo-electron microscopy structures of the Bag1-bound 26S proteasome, revealing unprecedented conformational rearrangements within the 19S regulatory ...
particle. Bag1 binding to the Rpn1 induces a marked reconfiguration of AAA+ adenosine triphosphatase (ATPase) ring, disrupting its canonical spiral staircase and remodeling the central channel architecture. This reconfiguration generates a large cavity above the substrate entry gate of the 20S core particle. The conserved pore-2 loops of ATPases Rpt2 and Rpt5 play critical roles in opening of the 20S gate, enabling substrate entry into proteolytic chamber independently of ubiquitination. These findings suggest a previously unknown mechanism of the proteasomal degradation, by which remodeling the central cavity and 20S gate in the presence of Bag1, possibly bypassing the need for ubiquitination.
Mesh Terms:
Adenosine Triphosphatases, Cryoelectron Microscopy, DNA-Binding Proteins, HSP70 Heat-Shock Proteins, Models, Molecular, Molecular Chaperones, Proteasome Endopeptidase Complex, Protein Binding, Protein Conformation, Proteolysis, Saccharomyces cerevisiae Proteins, Substrate Specificity, Transcription Factors
Sci Adv
Date: Feb. 20, 2026
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