Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins

Cell. 2006 Jul 28;126(2):361-73. doi: 10.1016/j.cell.2006.05.043.

Abstract

Many misfolded endoplasmic reticulum (ER) proteins are eliminated by ERAD, a process in which substrates are polyubiquitylated and moved into the cytosol for proteasomal degradation. We have identified in S. cerevisiae distinct ubiquitin-ligase complexes that define different ERAD pathways. Proteins with misfolded ER-luminal domains use the ERAD-L pathway, in which the Hrd1p/Hrd3p ligase forms a near stoichiometric membrane core complex by binding to Der1p via the linker protein Usa1p. This core complex associates through Hrd3p with Yos9p, a substrate recognition protein in the ER lumen. Substrates with misfolded intramembrane domains define a pathway (ERAD-M) that differs from ERAD-L by being independent of Usa1p and Der1p. Membrane proteins with misfolded cytosolic domains use the ERAD-C pathway and are directly targeted to the Doa10p ubiquitin ligase. All three pathways converge at the Cdc48p ATPase complex. These results lead to a unifying concept for ERAD that may also apply to mammalian cells.

Publication types

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

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins / metabolism
  • Endoplasmic Reticulum / metabolism*
  • Fungal Proteins / metabolism*
  • Ligases / metabolism*
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins / metabolism
  • Models, Biological
  • Protein Folding
  • Protein Structure, Tertiary
  • Proteins / metabolism*
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / metabolism
  • Substrate Specificity
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases / metabolism
  • Valosin Containing Protein

Substances

  • Carrier Proteins
  • Cell Cycle Proteins
  • DER1 protein, S cerevisiae
  • EXO84 protein, S cerevisiae
  • Fungal Proteins
  • HRD3 protein, S cerevisiae
  • Membrane Glycoproteins
  • Membrane Proteins
  • Proteins
  • Saccharomyces cerevisiae Proteins
  • Ubiquitin
  • Yos9 protein, S cerevisiae
  • HRD1 protein, S cerevisiae
  • SSM4 protein, S cerevisiae
  • Ubiquitin-Protein Ligases
  • Adenosine Triphosphatases
  • CDC48 protein, S cerevisiae
  • Valosin Containing Protein
  • Ligases