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Substrate recognition in ER‐associated degradation mediated by Eps1, a member of the protein disulfide isomerase family
Author(s) -
Wang Qiongqing,
Chang Amy
Publication year - 2003
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdg378
Subject(s) - endoplasmic reticulum associated protein degradation , biology , protein disulfide isomerase , ubiquitin ligase , microbiology and biotechnology , transmembrane protein , transmembrane domain , ubiquitin , chaperone (clinical) , biochemistry , endoplasmic reticulum , unfolded protein response , membrane , gene , medicine , pathology , receptor
Pma1‐D378N is a misfolded plasma membrane protein in yeast that is prevented from delivery to the cell surface and targeted instead for ER‐associated degradation (ERAD). Degradation of Pma1‐D378N is dependent on the ubiquitin ligase Doa10 and the ubiquitin chaperone Cdc48. Recognition of Pma1‐D378N by the ERAD pathway is dependent on Eps1, a transmembrane member of the protein disulfide isomerase (PDI) oxidoreductase family. Eps1 has two thioredoxin‐like domains containing a CPHC and a CDKC active site. Although Eps1 interaction with wild‐type Pma1 was not detected, Eps1 co‐immunoprecipitates with Pma1‐D378N. Eps1 interaction with Pma1‐D378N requires the CPHC motif, although both thioredoxin‐like domains appear to cooperate in substrate recognition. In the absence of the native transmembrane domain and cytoplasmic tail of Eps1, degradation of Pma1‐D378N is slowed, suggesting that Eps1 facilitates presentation of substrate to membrane‐bound components of the degradation machinery. Genetic interactions with other mutants of the ERAD machinery and induction of the unfolded protein response in eps1 Δ cells support a general role for Eps1 as a recognition component of the ERAD pathway.