Chaperone-mediated pathway of proteasome regulatory particle assembly

Nature. 2009 Jun 11;459(7248):861-5. doi: 10.1038/nature08063.

Abstract

The proteasome is a protease that controls diverse processes in eukaryotic cells. Its regulatory particle (RP) initiates the degradation of ubiquitin-protein conjugates by unfolding the substrate and translocating it into the proteasome core particle (CP) to be degraded. The RP has 19 subunits, and their pathway of assembly is not understood. Here we show that in the yeast Saccharomyces cerevisiae three proteins are found associated with RP but not with the RP-CP holoenzyme: Nas6, Rpn14 and Hsm3. Mutations in the corresponding genes confer proteasome loss-of-function phenotypes, despite their virtual absence from the holoenzyme. These effects result from deficient RP assembly. Thus, Nas6, Rpn14 and Hsm3 are RP chaperones. The RP contains six ATPases-the Rpt proteins-and each RP chaperone binds to the carboxy-terminal domain of a specific Rpt. We show in an accompanying study that RP assembly is templated through the Rpt C termini, apparently by their insertion into binding pockets in the CP. Thus, RP chaperones may regulate proteasome assembly by directly restricting the accessibility of Rpt C termini to the CP. In addition, competition between the RP chaperones and the CP for Rpt engagement may explain the release of RP chaperones as proteasomes mature.

Publication types

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

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Conserved Sequence
  • Evolution, Molecular
  • Holoenzymes / chemistry
  • Holoenzymes / metabolism
  • Humans
  • Models, Molecular
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Mutation
  • Phenotype
  • Proteasome Endopeptidase Complex / chemistry*
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism

Substances

  • Carrier Proteins
  • HSM3 protein, S cerevisiae
  • Holoenzymes
  • Molecular Chaperones
  • NAS6 protein, S cerevisiae
  • PSMD10 protein, human
  • Proto-Oncogene Proteins
  • Saccharomyces cerevisiae Proteins
  • PSMC4 protein, human
  • Proteasome Endopeptidase Complex
  • Rpn14 protein, S cerevisiae
  • Adenosine Triphosphatases
  • ATPases Associated with Diverse Cellular Activities