A major site of QCAP is the endoplasmic reticulum membrane where several UPS complexes are responsible for the ubiquitination of misfolded substrates, a process termed ER-Associated Degradation (ERAD).

In yeast, two ubiquitylation complexes are present at the endoplasmic reticulum membrane and they are named by the E3 ligases involved, HRD1 and doa10. Each of the complexes recognizes a distinct set of substrates, with minor overlaps. The common E2 enzyme, Ubc7, operates with both E3 complexes Doa10 and Hrd1, while Ubc6 operates only with the Doa10 E3 ligase.

How these enzymes cooperate during ubiquitination by the Doa10 pathway was unknown, until we solved the issue in 2016 by demonstrating the distinct role of each E2 enzyme (Weber et al., Mol Cell 2016). We further demonstrated that the E2 enzyme Ubc7 is activated differently by the two different E3 ligase complexes, findings that represent a previously unidentified mechanism for regulating protein ubiquitination (Cohen et al., 2015).