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A conserved ubiquitin ligase of the nuclear envelope/endoplasmic reticulum that functions in both ER-associated and Matalpha2 repressor degradation.

Abstract
Substrate discrimination in the ubiquitin-proteasome system is believed to be dictated by specific combinations of ubiquitin-protein ligases (E3s) and ubiquitin-conjugating enzymes (E2s). Here we identify Doa10/Ssm4 as a yeast E3 that is embedded in the endoplasmic reticulum (ER)/nuclear envelope yet can target the soluble transcription factor Matalpha2. Doa10 contains an unusual RING finger, which has ubiquitin-ligase activity in vitro and is essential in vivo for degradation of alpha2 via its Deg1 degradation signal. Doa10 functions with two E2s, Ubc6 and Ubc7, to ubiquitinate Deg1-bearing substrates, and it is also required for the degradation of at least one ER membrane protein. Interestingly, different short-lived ER proteins show distinct requirements for Doa10 and another ER-localized E3, Hrd1. Nevertheless, the two E3s overlap in function: A doa10Delta hrd1Delta mutant is far more sensitive to cadmium relative to either single mutant and displays strong constitutive induction of the unfolded protein response; this suggests a role for both E3s in eliminating aberrant ER proteins. The likely human ortholog of DOA10 is in the cri-du-chat syndrome critical region on chromosome 5p, suggesting that defective ubiquitin ligation might contribute to this common genetic disorder.
AuthorsR Swanson, M Locher, M Hochstrasser
JournalGenes & development (Genes Dev) Vol. 15 Issue 20 Pg. 2660-74 (Oct 15 2001) ISSN: 0890-9369 [Print] United States
PMID11641273 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Fungal Proteins
  • Homeodomain Proteins
  • MATA2 protein, S cerevisiae
  • Multienzyme Complexes
  • Repressor Proteins
  • Saccharomyces cerevisiae Proteins
  • Ubiquitin
  • HRD1 protein, S cerevisiae
  • Ubiquitin-Protein Ligases
  • Cysteine Endopeptidases
  • Intramolecular Transferases
  • DEG1 protein, S cerevisiae
  • Ligases
Topics
  • Amino Acid Sequence
  • Cysteine Endopeptidases (metabolism)
  • Endoplasmic Reticulum (metabolism, ultrastructure)
  • Fluorescent Antibody Technique
  • Fungal Proteins (metabolism)
  • Genetic Vectors
  • Homeodomain Proteins (metabolism)
  • Immunoblotting
  • Intramolecular Transferases
  • Ligases (metabolism)
  • Molecular Sequence Data
  • Multienzyme Complexes (metabolism)
  • Nuclear Envelope (metabolism, ultrastructure)
  • Protein Conformation
  • Repressor Proteins (metabolism)
  • Saccharomyces cerevisiae (enzymology, metabolism)
  • Saccharomyces cerevisiae Proteins
  • Sequence Homology, Amino Acid
  • Substrate Specificity
  • Ubiquitin (metabolism)
  • Ubiquitin-Protein Ligases

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