biostudies-literatureLin LLU.S. Department of Health & Human Services | NIH | National Institute of General Medical SciencesU.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases2064https://www.ebi.ac.uk/biostudies/studies/S-EPMC12949252biostudies-literatureUnknown17(1)The SEL1L-HRD1 complex represents the most conserved branch of endoplasmic reticulum (ER)-associated degradation (ERAD), a critical quality-control pathway that clears misfolded ER proteins. However, the molecular organization and pathogenic mechanisms of mammalian ERAD have remained elusive. Here, we report the cryo-EM structure of the core mammalian ERAD complex, comprising the ER lectin OS9, SEL1L, and the E3 ubiquitin ligase HRD1. The structure, validated by mutagenesis and crosslinking assays, reveals a dimeric assembly of the core complex in which SEL1L and OS9 form a claw-like configuration in the ER lumen that mediates substrate engagement, while HRD1 dimerizes within the membrane that may facilitate substrate translocation. Furthermore, pathogenic SEL1L mutations at the SEL1L-OS9 Nature communicationsStructural basis and pathological implications of the dimeric OS9-SEL1L-HRD1 ERAD Core Complex.PMC12949252R35GM130292R01DK120047R01DK120330Qi LLin LLMaldosevic EJomaa AZhou LEfalseStructural basis and pathological implications of the dimeric OS9-SEL1L-HRD1 ERAD Core Complex.The SEL1L-HRD1 complex represents the most conserved branch of endoplasmic reticulum (ER)-associated degradation (ERAD), a critical quality-control pathway that clears misfolded ER proteins. However, the molecular organization and pathogenic mechanisms of mammalian ERAD have remained elusive. Here, we report the cryo-EM structure of the core mammalian ERAD complex, comprising the ER lectin OS9, SEL1L, and the E3 ubiquitin ligase HRD1. The structure, validated by mutagenesis and crosslinking assays, reveals a dimeric assembly of the core complex in which SEL1L and OS9 form a claw-like configuration in the ER lumen that mediates substrate engagement, while HRD1 dimerizes within the membrane that may facilitate substrate translocation. Furthermore, pathogenic SEL1L mutations at the SEL1L-OS9 2026-01-01T00:00:00Z2026 Jan2026-07-16T23:28:30.311Z2026-07-12T03:11:14.607ZS-EPMC129492524159306510.1038/s41467-026-68777-7