Endoplasmic reticulum (ER)-associated degradation (ERAD) of misfolded proteins of the secretory pathway is crucial for ER homeostasis and the physiological importance of this mechanism is reflected by more than 60 diseases that have been linked to ERAD to date. The best characterised mammalian ERAD complex is centred on the ubiquitin ligase Hrd1, and for a complete understanding of the dynamics of the ERAD network it is important to thoroughly characterise the interactions within the Hrd1 complex and to decipher the functions of the individual accessory factors. SEL1L is a well characterised interaction partner of Hrd1 and here we identify a highly hydrophobic region in the lumenal part of SEL1L as necessary, but not sufficient, to interact with Hrd1; as a consequence, the topology of SEL1L may need to be re-evaluated. Furthermore, we investigate the roles of the novel Hrd1 interaction partners AUP1 and FAM8A1 in ERAD. We establish here that AUP1 adds to the complexity of the ERAD network by making the cognate E2 of gp78, Ube2g2, accessible to Hrd1 and by regulating the access of polyubiquitinated proteins to the Hrd1 complex. Moreover, we demonstrate that Hrd1 is the regulator of FAM8A1 half-life and that the interaction between these two proteins is necessary for degradation of the lumenal ERAD model substrate TTR<sub>D18G</sub>.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:629489 |
| Date | January 2013 |
| Creators | Schulz, Jasmin |
| Contributors | Christianson, John C. |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:fc156e42-bc32-4725-9cab-2e7cbfe61869 |
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