E3 ubiquitin ligase (wikipedia), in ER membrane

  • When overexpressed, the yeast Hrd1p protein can autonomously carry out degradation of soluble substrates within the ER lumen (Carvalho et al., 2010; Cell)
  • Overexpression of Hrd1p without its adaptors is toxic to cells, apparently because of uncontrolled and inappropriate degradation of many proteins (Denic et al., 2006; Cell)
  • Hrd1p autoubiquitylates and thus triggers its own degradation (--> in a complex with Hrd3p the auto-ubiquitylation is inhibited)
  • in mammalian cells it seems to be the other way round: HRD1 appears to stabilize SEL1L
  • Via residues in its transmembrane domains, Hrd1p directly recognizes proteins that misfold within the ER membrane (Sato et al., 2009; Mol Cell)