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Endoplasmic Reticulum Chaperone Proteins Calnexin and ERp57: Structure and Function Open Access


Other title
endoplasmic reticulum
Type of item
Degree grantor
University of Alberta
Author or creator
Coe, Helen
Supervisor and department
Michalak, Marek (Biochemistry) (Pediatrics)
Examining committee member and department
Thebaud, Bernard (Pediatrics)
Michalak, Marek (Biochemistry) (Pediatrics)
Dyck, Jason (Pediatrics)
Turksen, Kursad (Biochemistry)
Melancon, Paul (Cell Biology)
Medical Sciences-Paediatrics

Date accepted
Graduation date
Doctor of Philosophy
Degree level
The endoplasmic reticulum is responsible for folding of newly synthesized proteins. Chaperone proteins, calreticulin and calnexin, with the thiol-oxidoreductase ERp57, interact with nascent proteins in a cycle of quality control to ensure proteins are folded correctly. In this study, we investigated the tissue-specific expression of both calnexin and ERp57 throughout embryonic development. We found that calnexin is primarily expressed in neurological tissue and cartilage which is not surprising considering that targeted deletion of calnexin results in live mice with severe motor defects. Targeted deletion of the Pdia3 gene, which encodes ERp57, in mice is embryonic lethal at embryonic day 13.5. ERp57 expressed mainly in lung, liver and neurological tissue suggesting that ERp57 may have a critical role in the development of these tissues. Both calnexin and ERp57 play a role in quality control and my findings suggest that calnexin- and ERp57-deficient cells are under persistent stress and adapt to maintain ER homeostasis during. We also show here that STAT3-dependent signalling is increased in the absence of ERp57 and this can be rescued by expression of ER-targeted ERp57 but not by cytoplasmic-targeted protein, indicating that ERp57 affects STAT3 signalling from the lumen of the ER. ERp57 effects on STAT3 signalling are enhanced by ER luminal complex formation between ERp57 and calreticulin. We also used site-specific mutagenesis to disrupt cysteine and histidine residues in the N- and P-domains of calnexin. We identified that disruption Cys161/195 in calnexin resulted in significant loss of its chaperone activity for glycoyslated substrates. Disruption of Cys361/367 also had minor impacts on the function of calnexin as chaperone for glycosylated substrates. Mutations to H202, Cys161/195 and Cys361/367 resulted in enhanced binding of ERp57 to calnexin. In conclusion, these observations suggest that the cysteine residues within calnexin are important to the structure and function of calnexin. Research presented in this thesis highlights the diversity of the functions of ER proteins calnexin and ERp57 and understanding the ER-associated molecular mechanisms within a cell will undoubtedly give us essential knowledge regarding healthy and normal development.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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