Ubiquitination is a pivotal, multi-step, enzymatic post-translational modification that conjugates ubiquitin into chains onto protein substrates. Ubiquitination triggers a plethora of biological signals, and our focus is on protein homeostasis achieved through degradation of misfolded, unassembled, and highly regulated proteins in the ER. The specificity and mechanism of interaction between ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s) is key to the combinatorial diversity in the proteome’s regulation pathway. The first prometastatic mammalian E3, gp78, functions with the E2 Ube2g2 in the process of endoplasmic reticulum associated degradation (ERAD). gp78 is a membrane protein that contains a cytosolic tail (comprising the ligase activity) consisting of three domains: the RING domain (responsible for ubiquitin transfer), the CUE domain (a ubiquitin binding domain), and the G2BR domain (a specific binding region to the cognate E2 (Ube2g2)). Previous work established the structures and interfaces of each domain of Ube2g2 and for the RING and G2BR in complex with Ube2g2 [Mol. Cell 2009, 2013; Structure 2012; EMBO J. 2013]. Allosteric and dynamic changes [Structure 2017] propose an overall structural model and mechanistic understanding. In order to advance the concerted mechanism, it is important to examine the entire molecular system consisting of the full cytoplasmic tail (gp78C) in complex with Ube2g2 and the Ub-ligated Ube2g2~Ub. Recent progress in expressing full length gp78C (30 kDa) coupled with flexible labeling protocols (15N/13C/2H and ILV-13CH3) enable triple-resonance NMR experiments for backbone assignments. Utilizing sortase ligation [PNAS 2011; J. Biomol. NMR 2011, 2015; Nature 2016], full length gp78C is segmentally labeled to enable NMR assignment and structural studies. Finally, to mimic the natural membrane environment, gp78C can be tethered onto a nanodisc membrane mimetic, where the mechanism of interactions among the three domains can be extensively studied by both NMR and biophysical techniques in the presence of Ube2g2.