Format

Send to

Choose Destination
Science. 2018 Oct 11. pii: eaav0725. doi: 10.1126/science.aav0725. [Epub ahead of print]

Substrate-engaged 26S proteasome structures reveal mechanisms for ATP-hydrolysis-driven translocation.

Author information

1
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
2
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
3
California Institute for Quantitative Biosciences, University of California at Berkeley, Berkeley, CA 94720, USA.
4
Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA 94720, USA.
5
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA. glander@scripps.edu a.martin@berkeley.edu.
6
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA. glander@scripps.edu a.martin@berkeley.edu.

Abstract

The 26S proteasome is the primary eukaryotic degradation machine and thus critically involved in numerous cellular processes. The hetero-hexameric ATPase motor of the proteasome unfolds and translocates targeted protein substrates into the open gate of a proteolytic core, while a proteasomal deubiquitinase concomitantly removes substrate-attached ubiquitin chains. However, the mechanisms by which ATP hydrolysis drives the conformational changes responsible for these processes have remained elusive. Here we present the cryo-EM structures of four distinct conformational states of the actively ATP-hydrolyzing, substrate-engaged 26S proteasome. These structures reveal how mechanical substrate translocation accelerates deubiquitination, and how ATP-binding, hydrolysis, and phosphate-release events are coordinated within the AAA+ motor to induce conformational changes and propel the substrate through the central pore.

PMID:
30309908
DOI:
10.1126/science.aav0725

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center