Structure and Function of the 26S Proteasome

Annu Rev Biochem. 2018 Jun 20:87:697-724. doi: 10.1146/annurev-biochem-062917-011931. Epub 2018 Apr 13.


As the endpoint for the ubiquitin-proteasome system, the 26S proteasome is the principal proteolytic machine responsible for regulated protein degradation in eukaryotic cells. The proteasome's cellular functions range from general protein homeostasis and stress response to the control of vital processes such as cell division and signal transduction. To reliably process all the proteins presented to it in the complex cellular environment, the proteasome must combine high promiscuity with exceptional substrate selectivity. Recent structural and biochemical studies have shed new light on the many steps involved in proteasomal substrate processing, including recognition, deubiquitination, and ATP-driven translocation and unfolding. In addition, these studies revealed a complex conformational landscape that ensures proper substrate selection before the proteasome commits to processive degradation. These advances in our understanding of the proteasome's intricate machinery set the stage for future studies on how the proteasome functions as a major regulator of the eukaryotic proteome.

Keywords: 26S proteasome; AAA+ ATPase; deubiquitination; energy-dependent protein degradation; ubiquitin code; ubiquitin receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / chemistry
  • ATPases Associated with Diverse Cellular Activities / metabolism
  • Deubiquitinating Enzymes / chemistry
  • Deubiquitinating Enzymes / metabolism
  • Humans
  • Models, Biological
  • Models, Molecular
  • Molecular Motor Proteins / chemistry
  • Molecular Motor Proteins / metabolism
  • Proteasome Endopeptidase Complex / chemistry*
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Conformation
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / metabolism
  • Substrate Specificity
  • Ubiquitin / chemistry
  • Ubiquitin / metabolism


  • Molecular Motor Proteins
  • Saccharomyces cerevisiae Proteins
  • Ubiquitin
  • Deubiquitinating Enzymes
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease
  • ATPases Associated with Diverse Cellular Activities