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.
|
Authors | R Swanson, M Locher, M Hochstrasser |
Journal | Genes & development
(Genes Dev)
Vol. 15
Issue 20
Pg. 2660-74
(Oct 15 2001)
ISSN: 0890-9369 [Print] United States |
PMID | 11641273
(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
|