Fig. 1 |. The Hrd1 complex and the schematic for Hrd1-dependent retrotranslocation of ERAD substrates.

a, Schematic of the Hrd1 multiprotein complex. A Hrd1 dimer associates with two molecules of Hrd3 (adapted from the cryo-EM structure⁵). On the lumenal side, Hrd3 associates with Kar2 and in turn Yos9, which survey the structures of nascent glycoproteins and then recruit misfolded substrates to the ERAD machinery. Along with Hrd1, Der1 also intimately contacts retrotranslocating polypeptides. Usa1 associates with Hrd1, promoting its dimerisation, and the cytosolic domain of Ubx2 recruits Cdc48, an AAA⁺−ATPase (not shown), to the Hrd1 complex for retrotranslocation. b, A model of Hrd1 substrate retrotranslocation and ubiquitination. i. Hrd1 is in the closed inactive state. ii. Hrd1 autoubiquitination (Ub) leads to initial channel formation. iii. Binding of a misfolded substrate to the lumenal side of Hrd1 further opens the channel, allowing for substrate (i.e., CPY*) insertion. iv. The presence of a high-affinity binding site on the cytosolic side of ubiquitinated Hrd1 drives substrate retrotranslocation. v. Retrotranslocated CPY* is ubiquitinated by Hrd1.