The membrane-associated E3 ligase complexes in yeast. (i) The Hrd1 “core” complex contains Hrd1, Hrd3, Usa1, and Der1. ERAD-L substrates are recognized by a lumenal Hsp70 (BiP; Kar2 in yeast), Yos9, and the lumenal domain of Hrd3. ERAD-M substrates may be directly recognized by the transmembrane domain of Hrd1. Recognized substrates are retrotranslocated to the cytosol and ubiquitylated by Ubc7 and Hrd1 before proteasomal degradation. (ii) Doa10 (TEB4 in mammals) ubiquitylates membrane substrates that have a misfolded domain facing the cytosol. Ubiquitylated membrane proteins may also be extracted to the cytosol and degraded by the proteasome.