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
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphatases / metabolism
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Carrier Proteins / metabolism
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Cell Cycle Proteins / metabolism
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Endoplasmic Reticulum / metabolism*
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Fungal Proteins / metabolism*
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Ligases / metabolism*
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Membrane Glycoproteins / chemistry
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Membrane Glycoproteins / metabolism
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Membrane Proteins / metabolism
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Models, Biological
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Protein Folding
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Protein Structure, Tertiary
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Proteins / metabolism*
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Saccharomyces cerevisiae / enzymology
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae / metabolism
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Saccharomyces cerevisiae Proteins / chemistry
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Saccharomyces cerevisiae Proteins / metabolism
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Substrate Specificity
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Ubiquitin / metabolism*
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Ubiquitin-Protein Ligases / metabolism
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Valosin Containing Protein
Substances
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Carrier Proteins
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Cell Cycle Proteins
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DER1 protein, S cerevisiae
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EXO84 protein, S cerevisiae
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Fungal Proteins
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HRD3 protein, S cerevisiae
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Membrane Glycoproteins
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Membrane Proteins
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Proteins
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Saccharomyces cerevisiae Proteins
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Ubiquitin
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Yos9 protein, S cerevisiae
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HRD1 protein, S cerevisiae
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SSM4 protein, S cerevisiae
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Ubiquitin-Protein Ligases
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Adenosine Triphosphatases
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CDC48 protein, S cerevisiae
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Valosin Containing Protein
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Ligases