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Exposed hydrophobicity is a key determinant of nuclear quality control degradation.

Protein quality control (PQC) degradation protects the cell by preventing the toxic accumulation of misfolded proteins. In eukaryotes, PQC degradation is primarily achieved by ubiquitin ligases that attach ubiquitin to misfolded proteins for proteasome degradation. To function effectively, PQC ubiquitin ligases must distinguish misfolded proteins from their normal counterparts by recognizing an attribute of structural abnormality commonly shared among misfolded proteins. However, the nature of the structurally abnormal feature recognized by most PQC ubiquitin ligases is unknown. Here we demonstrate that the yeast nuclear PQC ubiquitin ligase San1 recognizes exposed hydrophobicity in its substrates. San1 recognition is triggered by exposure of as few as five contiguous hydrophobic residues, which defines the minimum window of hydrophobicity required for San1 targeting. We also find that the exposed hydrophobicity recognized by San1 can cause aggregation and cellular toxicity, underscoring the fundamental protective role for San1-mediated PQC degradation of misfolded nuclear proteins.

Pubmed ID: 21551067


  • Fredrickson EK
  • Rosenbaum JC
  • Locke MN
  • Milac TI
  • Gardner RG


Molecular biology of the cell

Publication Data

July 1, 2011

Associated Grants

  • Agency: NIGMS NIH HHS, Id: 5T32GM007750
  • Agency: NIA NIH HHS, Id: R01 AG031136
  • Agency: NIA NIH HHS, Id: R01AG031136

Mesh Terms

  • Cell Nucleus
  • Hydrophobic and Hydrophilic Interactions
  • Nuclear Proteins
  • Proteasome Endopeptidase Complex
  • Protein Folding
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Ubiquitin
  • Ubiquitin-Protein Ligases