Figure 7.

Current model of cholesterol-accelerated degradation of SM N100. SM N100 senses cholesterol levels in the ER membrane via a re-entrant loop and an amphipathic helix. With excess cholesterol, the amphipathic helix is pushed out of the ER membrane, exposing a hydrophobic patch contributing to increased disorder. The lengthened disordered region includes residues Ser-59, Ser-61, Ser-83, and Ser-87 (in yellow stars), which may all serve as ubiquitination sites, although Ser-83 was the only non-canonical ubiquitination site formally identified in this work. The MARCH6 E3 ubiquitin ligase most likely ubiquitinates Ser-83, and perhaps also Ser-59, Ser-61, and Ser-87, to mediate the cholesterol-accelerated degradation of the SM N100 degron.