Structures of the 26 <i>S</i> 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 26 S proteasome, recruiting Hsp70-bound clients for proteasomal degradation. Here, we present cryo–electron microscopy structures of the Bag1-bound 26 S proteasome, revealing unprecedented conformational rearrangements within the 19 S 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 20 S core particle. The conserved pore-2 loops of ATPases Rpt2 and Rpt5 play critical roles in opening of the 20 S 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 20 S gate in the presence of Bag1, possibly bypassing the need for ubiquitination.