Osteopetrosis is characterized by increased bone density and fragility. The R444L missense mutation in the human V-ATPase a3 subunit causes this disease. Modeling the R444L mutation in mouse a3 caused endoplasmic reticulum (ER) retention of a3 with attendant abrogation of maturation and trafficking of the glycoprotein and its degradation. The mutant protein also displayed altered conformation and increased degradation. Together, these data suggest that R444 is involved in protein folding or stability significant to mammalian a3, and that infantile osteopetrosis caused by the R444L mutation in the V-ATPase a3 subunit is another member of the growing class of protein folding diseases. We also ascertained that the N-Glycosylation sites of the a3 glycoprotein lie at position N484 and N504, data that help to refine the topology of the a subunit. Overall, this study sheds new light onto the role that R444 plays in a subunit structure, and refines a subunit topology.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/32458 |
| Date | 19 July 2012 |
| Creators | Bhargava, Ajay |
| Contributors | Manolson, Morris Frank |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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