Molecular architecture of the 26S proteasome holocomplex determined by an integrative approach

Keren Lasker, Friedrich Förster, Stefan Bohn, Thomas Walzthoeni, Elizabeth Villa, Pia Unverdorben, Florian Beck, Ruedi Aebersold, Andrej Sali, Wolfgang Baumeister

Research output: Contribution to journalArticleAcademicpeer-review


The 26S proteasome is at the executive end of the ubiquitin-proteasome pathway for the controlled degradation of intracellular proteins. While the structure of its 20S core particle (CP) has been determined by X-ray crystallography, the structure of the 19S regulatory particle (RP), which recruits substrates, unfolds them, and translocates them to the CP for degradation, has remained elusive. Here, we describe the molecular architecture of the 26S holocomplex determined by an integrative approach based on data from cryoelectron microscopy, X-ray crystallography, residue-specific chemical cross-linking, and several proteomics techniques. The "lid" of the RP (consisting of Rpn3/5/6/7/8/9/11/12) is organized in a modular fashion. Rpn3/5/6/7/9/12 form a horseshoe-shaped heterohexamer, which connects to the CP and roofs the AAA-ATPase module, positioning the Rpn8/Rpn11 heterodimer close to its mouth. Rpn2 is rigid, supporting the lid, while Rpn1 is conformationally variable, positioned at the periphery of the ATPase ring. The ubiquitin receptors Rpn10 and Rpn13 are located in the distal part of the RP, indicating that they were recruited to the complex late in its evolution. The modular structure of the 26S proteasome provides insights into the sequence of events prior to the degradation of ubiquitylated substrates.

Original languageEnglish
Pages (from-to)1380-7
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number5
Publication statusPublished - 31 Jan 2012
Externally publishedYes


  • Cryoelectron Microscopy
  • Crystallography, X-Ray
  • Mass Spectrometry
  • Models, Molecular
  • Proteasome Endopeptidase Complex
  • Protein Conformation
  • Proteomics
  • Schizosaccharomyces
  • Substrate Specificity


Dive into the research topics of 'Molecular architecture of the 26S proteasome holocomplex determined by an integrative approach'. Together they form a unique fingerprint.

Cite this