{"doi":"10.1126/science.aaz2449","title":"Structural basis of ER-associated protein degradation mediated by the Hrd1 ubiquitin ligase complex","abstract":"Misfolded luminal endoplasmic reticulum (ER) proteins undergo ER-associated degradation (ERAD-L): They are retrotranslocated into the cytosol, polyubiquitinated, and degraded by the proteasome. ERAD-L is mediated by the Hrd1 complex (composed of Hrd1, Hrd3, Der1, Usa1, and Yos9), but the mechanism of retrotranslocation remains mysterious. Here, we report a structure of the active Hrd1 complex, as determined by cryo-electron microscopy analysis of two subcomplexes. Hrd3 and Yos9 jointly create a luminal binding site that recognizes glycosylated substrates. Hrd1 and the rhomboid-like Der1 protein form two \"half-channels\" with cytosolic and luminal cavities, respectively, and lateral gates facing one another in a thinned membrane region. These structures, along with crosslinking and molecular dynamics simulation results, suggest how a polypeptide loop of an ERAD-L substrate moves through the ER membrane.","journal":"Science","year":2020,"id":49576,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":246,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9499,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":240037,"name":"Marc Siggel","orcid":"0000-0003-3393-4988","position":1,"is_corresponding":false},{"id":56800,"name":"Sergey Ovchinnikov","orcid":"0000-0003-2774-2744","position":2,"is_corresponding":false},{"id":240038,"name":"Wei Mi","orcid":"0000-0002-2845-4608","position":3,"is_corresponding":false},{"id":240039,"name":"Vladimir Svetlov","orcid":"0000-0002-1977-4271","position":4,"is_corresponding":false},{"id":240040,"name":"Evgeny Nudler","orcid":"0000-0002-8811-3071","position":5,"is_corresponding":false},{"id":240041,"name":"Maofu Liao","orcid":"0000-0002-3481-450X","position":6,"is_corresponding":false},{"id":240042,"name":"Gerhard Hummer","orcid":"0000-0001-7768-746X","position":7,"is_corresponding":false},{"id":240043,"name":"Tom A. Rapoport","orcid":"0000-0001-9911-4216","position":8,"is_corresponding":false},{"id":240036,"name":"Xudong Wu","orcid":"0000-0002-6492-2202","position":0,"is_corresponding":true}],"reference_count":98,"raw_metadata":null,"created_at":"2026-07-18T20:37:28.027635Z","pmid":"32327568","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}