{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T04:38:23Z","timestamp":1791088703922,"version":"4.1.0"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"2","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2006,1,10]]},"abstract":"<jats:p>\n                    Efficient targeting of proteins for degradation from the secretory pathway is essential to homeostasis. This occurs through endoplasmic reticulum (ER)-associated degradation (ERAD). In this study, we establish that a human ubiquitin ligase (E3), gp78, and a specific E2, Ube2g2, are both critically important for ERAD of multiple substrates. gp78 exhibits a complex domain structure that, in addition to the RING finger, includes a ubiquitin-binding Cue domain and a specific binding site for Ube2g2. Disruption of either of these domains abolishes gp78-mediated ubiquitylation and protein degradation, resulting in accumulation of substrates in their fully glycosylated forms in the ER. This suggests that gp78-mediated ubiquitylation is an early step in ERAD that precedes dislocation of substrates from the ER. The\n                    <jats:italic>in vivo<\/jats:italic>\n                    requirement for both an E2-binding site distinct from the RING finger and a ubiquitin-binding domain intrinsic to an E3 suggests a previously unappreciated level of complexity in ubiquitin ligase function. These results also provide proof of principle that interrupting a specific E2-E3 interaction can selectively inhibit ERAD.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0506618103","type":"journal-article","created":{"date-parts":[[2006,1,3]],"date-time":"2006-01-03T21:13:40Z","timestamp":1136322820000},"page":"341-346","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":196,"title":["The activity of a human endoplasmic reticulum-associated degradation E3, gp78, requires its Cue domain, RING finger, and an E2-binding site"],"prefix":"10.1073","volume":"103","author":[{"given":"Bo","family":"Chen","sequence":"first","affiliation":[{"name":"Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, Building 560, Room 22-103, National Cancer Institute, Frederick, MD 21702"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Mariano","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, Building 560, Room 22-103, National Cancer Institute, Frederick, MD 21702"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yien Che","family":"Tsai","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, Building 560, Room 22-103, National Cancer Institute, Frederick, MD 21702"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna H.","family":"Chan","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, Building 560, Room 22-103, National Cancer Institute, Frederick, MD 21702"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mickael","family":"Cohen","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, Building 560, Room 22-103, National Cancer Institute, Frederick, MD 21702"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan M.","family":"Weissman","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, Building 560, Room 22-103, National Cancer Institute, Frederick, MD 21702"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2006,1,3]]},"reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(02)00358-7"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg227"},{"key":"e_1_3_2_3_2","first-page":"39","volume":"223","year":"2003","unstructured":"Jarosch, E., Lenk, U. & Sommer, T. 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