The work in this thesis involves characterization of a novel Streptococcus agalactiae-secreted protein, skizzle, and its interactions with key proteins of the human fibrinolytic system. Skizzle binds human plasminogen (Pg) with high affinity and acts as a cofactor of Pg activation to form the clot-dissolving protease, plasmin. As a cofactor, skizzle uses two different mechanisms to enhance Pg activation by the endogenous Pg activators, urokinase and tissue-type plasminogen activator. Skizzle-enhanced Pg activation by urokinase is specific for the circulating, unmodified form, [Glu]Pg, and involves a skizzle-induced Pg conformational change to a more-easily activated conformation. Enhanced activation of both unmodified [Glu]Pg and modified [Lys]Pg by tissue-type plasminogen activator involves formation of a skizzle-containing ternary or quaternary complex with Pg and tissue-type plasminogen activator, resulting in enhanced Pg activation. To our knowledge, skizzle is the first S. agalactiae-secreted cofactor of human Pg activation. Skizzle has the potential to be a virulence factor in the pathogenesis of life-threatening S. agalactiae infections of newborns and immune-compromised adults.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-09062010-113724 |
| Date | 06 September 2010 |
| Creators | Wiles, Karen Godfrey |
| Contributors | Richard Hoover, Ingrid Verhammer, David Gailani, Andrzej Krezel, Eric Skaar, Paul E. Bock (advisor) |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu//available/etd-09062010-113724/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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