Fig. 7: Model for regulation of the ubiquitination cascade by membrane composition.

UBE2J2 adopts different conformations dependent on the membrane environment, thereby controlling its activity. Hydrophobic interactions between the cytosolic region of UBE2J2 and the membrane stabilize an auto-inhibited conformation. In the active state (left), the cytosolic region is accessible for E1-mediated loading. Membranes enriched in unsaturated lipids, exhibit packing defects (top), stabilizing an inactive UBE2J2 conformation that impairs interaction with the E1 and E3 enzymes. Increasing local UBE2J2 concentration overrides this inhibition via dimerization, promoting interaction with E1 and an E3 (middle). Increasing lipid saturation enhances lipid packing and favors an active UBE2J2 conformation. Ubiquitin loading of UBE2J2 and physical interaction with its cognate E3s, including RNF145, is enhanced (bottom). RNF145 is directly regulated by cholesterol, which might promote its oligomerization and auto-ubiquitination (right).