Authors
Maestro-Lopez M, Cheng TC, Muntaner J, Menendez M, Alonso M, Schweitzer A, Cuellar J, Valpuesta JM, Sakata E
Journal
BioRxiv
Citation
bioRxiv 2025.01.22.633148.
Abstract
The 26S proteasome primarily degrades proteins marked by polyubiquitin chains. Although ubiquitin-independent pathways for proteasomal degradation exist, the mechanisms involved remain poorly understood. Bag1 links the Hsp70 chaperone to the 26S proteasome, recruiting Hsp70-bound aberrant proteins for degradation. Here, we present high-resolution cryo-EM structures of the Bag1-bound 26S proteasome, which reveal unprecedented conformational changes within the 19S regulatory particle. Bag1 binding to the Rpn1 subunit induces a dramatic reconfiguration of AAA+ ATPase subunits, disrupting the canonical spiral staircase conformation and remodeling the central channel architecture. This creates a large cavity above the substrate entry gate of the 20S core particle, enabling the direct entry of Hsp70 clients into the proteolytic chamber. Thus, in this ubiquitin-independent degradation pathway, unfolded proteins can bypass the need for both client ubiquitination and ATP hydrolysis for degradation.
