ER retrotranslocon for misfolded luminal ER proteins.  Uses the ERAD-associated E3 ubiquitin-protein ligase, Hrd1p, which promotes polypeptide movement through the ER membrane (Carvalho et al., 2010; Bolte et al., 2011). As determined by cryoEM, Hrd1 is an 8 TMS dimer that associates with Hrd3 on the luminal side of the ER membrane to seal the channel used for protein retrotranslocation (Schoebel et al., 2017). The protein-conducting channel, Hrd1, is a ubiquitin ligase that serves as the transmembrane channel (Wu and Rapoport, 2018). The Cdc48/p97 ATPase pulls the unfolded substrate through the channel, out of the membrane. Cdc48 has a central pore, and the substrate protein passes from the cis side to the trans side (Wu and Rapoport, 2018). Otu1, ubiquitin thio ligase, partially de-ubiquitinates the substrate protein. The E3 ubiquitin-protein ligase accepts ubiquitin specifically from endoplasmic reticulum-associated UBC6 and UBC7 E2 ligases, and transfers it to substrates, promoting their degradation. It mediates the degradation of a broad range of substrates, including endoplasmic reticulum membrane proteins, soluble nuclear proteins and soluble cytoplasmic proteins. The DOA10 ubiquitin ligase complex is part of the ERAD-C pathway responsible for the rapid degradation of membrane proteins with misfolded cytoplasmic domains (Ravid et al., 2006). The 3-D structure of the Hrd1 complex (including Hrd1, Hrd3, Der1, Usa1 and Yos9) has been solved (Wu et al. 2020). It mediates the retrotranslocation of the polypeptide into the cytosol, which it is polyubiqutinated, extracted from the membrane by the Cdc48 ATPase complex and degraded by a proteosome. The importance of Hrd1 complex integrity during ERAD, suggests that allosteric interactions between transmembrane domains regulate Hrd1 complex formation (Nakatsukasa et al. 2022).