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Permanent link (DOI): https://doi.org/10.7939/R3P40F

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Palmitoylation targets calnexin to the MAM and regulates its functions Open Access

Descriptions

Other title
Subject/Keyword
palmitoylation
calnexin
calcium signaling
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Lynes, Emily Marian
Supervisor and department
Simmen, Thomas (Cell Biology)
Examining committee member and department
LaPointe, Paul (Cell Biology)
Hobman, Tom (Cell Biology)
Vance, Jean (Medicine)
Colberg-Poley, Anamaris (Pediatrics, George Washington University)
Department
Department of Cell Biology
Specialization

Date accepted
2013-01-28T11:08:31Z
Graduation date
2013-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
The mitochondria associated membranes (MAMs) of the endoplasmic reticulum (ER) are the points of contact between the ER, which is the organelle responsible for lipid and secreted protein synthesis and calcium storage, and the mitochondria, which are organelles responsible for cellular energy production. The MAM has many roles including the transfer of lipids and metabolites between these two organelles, as well as the mediation of calcium signaling between the ER and mitochondria. Calcium transfer at MAMs is of vital importance as it regulates mitochondrial metabolism and apoptosis, or programmed cell death. Although the MAM has been well-characterized in recent years, very little is currently known about how proteins target there and how these contact sites are maintained. In this thesis, I have identified a novel MAM targeting mechanism, palmitoylation, using a chimeric mutagenesis strategy. I have also identified two proteins, TMX and calnexin, which use this signal to target to MAM. Furthermore, I have characterized the role of calnexin at MAM by overexpressing wildtype and non-palmitoylatable calnexin in calnexin knockout cells. This led to the discovery that calnexin plays a role in ER-mitochondria calcium transfer and may affect structural changes at MAM during cellular stress. These findings have implications for the study of diseases where mitochondrial metabolism and deregulated cell death are factors, for example cancer and neurodegenerative disease.
Language
English
DOI
doi:10.7939/R3P40F
Rights
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.
Citation for previous publication
Lynes, E.M. and T. Simmen. (2011) Urban planning of the endoplasmic reticulum (ER): How diverse mechanisms segregate the many functions of the ER. Biochim Biophys Acta. 1813: 1893-905.Simmen, T., Lynes, E.M., Gesson, K., and G. Thomas. (2010) Oxidative protein folding in the endoplasmic reticulum: Tight links to the mitochondria-associated membrane (MAM). Biochim Biophys Acta. 1798: 1465-73.Myhill, N., Lynes, E.M., Nanji, J.A., Blagoveshchenskaya, A.D., Fei, H., Carmine Simmen, K., Cooper, T.J., Thomas, G. and T. Simmen. (2008) The subcellular distribution of calnexin is mediated by PACS-2. Mol Biol Cell. 19: 2777-88.Lynes, E.M., Bui, M., Yap, M.C., Benson, M.D., Schneider, B., Ellgaard, L., Berthiaume, L.G. and T. Simmen. (2011) Palmitoylated TMX and calnexin target to the mitochondria associated membrane. Embo J. 31: 457-70.

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