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Eukaryotic 20S proteasome catalytic subunit propeptides prevent active site inactivation by N-terminal acetylation and promote particle assembly.

Proteins targeted for degradation by the ubiquitin-proteasome system are degraded by the 26S proteasome. The core of this large protease is the 20S proteasome, a barrel-shaped structure made of a stack of four heptameric rings. Of the 14 different subunits that make up the yeast 20S proteasome, three have proteolytic active sites: Doa3/beta5, Pup1/beta2 and Pre3/beta1. Each of these subunits is synthesized with an N-terminal propeptide that is autocatalytically cleaved during particle assembly. We show here that the propeptides have both common and distinct functions in proteasome biogenesis. Unlike the Doa3 propeptide, which is crucial for proteasome assembly, the Pre3 and Pup1 propeptides are dispensable for cell viability and proteasome formation. However, mutants lacking these propeptide-encoding elements are defective for specific peptidase activities, are more sensitive to environmental stresses and have subtle defects in proteasome assembly. Unexpectedly, a critical function of the propeptide is the protection of the N-terminal catalytic threonine residue against Nalpha-acetylation. For all three propeptide-deleted subunits, activity of the affected catalytic center is fully restored when the Nat1-Ard1 Nalpha-acetyltransferase is mutated. In addition to delineating a novel function for proteasome propeptides, these data provide the first biochemical evidence for the postulated participation of the alpha-amino group in the proteasome catalytic mechanism.

Pubmed ID: 10393174

Authors

  • Arendt CS
  • Hochstrasser M

Journal

The EMBO journal

Publication Data

July 1, 1999

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM46904

Mesh Terms

  • Acetylation
  • Amino Acid Sequence
  • Arylamine N-Acetyltransferase
  • Binding Sites
  • Catalysis
  • Catalytic Domain
  • Cell Division
  • Cysteine Endopeptidases
  • Endopeptidases
  • Fungal Proteins
  • Isoenzymes
  • Molecular Sequence Data
  • Multienzyme Complexes
  • Peptide Fragments
  • Phenotype
  • Proteasome Endopeptidase Complex
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Sequence Deletion
  • Threonine