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Title: Molecular mechanism of Asi-mediated protein quality control
Author: Natarajan, Nivedita
ISNI:       0000 0004 8508 0221
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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Misfolded proteins in the membrane and lumen of the endoplasmic reticulum (ER) are eliminated by a quality control system called ER-associated protein degradation (ERAD). ERAD comprises several branches, each dependent on a different ubiquitin ligase complex with a preference for a particular type of misfolded protein. A third ERAD branch in Saccharomyces cerevisiae acting specifically at the inner nuclear membrane (INM) was uncovered. The core component of this branch is the Asi complex, consisting of the ubiquitin ligases Asi1 and Asi3 and the accessory protein Asi2. Asi complex promotes the degradation of ER proteins that mistarget to the INM and misfolded proteins thereby contributing to the quality control at the INM. However, how these proteins are unnoticed by ER ubiquitin ligases and selectively recognised by the Asi complex at the INM is unclear. We found that unassembled subunits of membrane complexes are prone to mislocalize to the INM and targeted by Asi complex for degradation. Using in vivo and in vitro studies, we show that recognition of the unassembled proteins is by direct binding of the transmembrane domain of the substrate to Asi2, subsequent ubiquitination by Asi1/3, extraction by the Cdc48 ATPase and finally degradation. Thus, our data suggest that protein complex assembly in the ER is facilitated by spatially restricting quality control of unassembled subunits to the INM. This INM quality control contributes to maintaining of the INM proteome identity and overall ER homeostasis.
Supervisor: Carvalho, Pedro Sponsor: EMBO
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Protein Quality Control