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Title page for ETD etd-09062010-113724

Type of Document Dissertation
Author Wiles, Karen Godfrey
URN etd-09062010-113724
Title Skizzle: a Novel Streptococcus agalactiae-secreted Cofactor of Human Plasminogen Activation
Degree PhD
Department Pathology
Advisory Committee
Advisor Name Title
Richard Hoover Committee Chair
Andrzej Krezel Committee Member
David Gailani Committee Member
Eric Skaar Committee Member
Ingrid Verhammer Committee Member
Paul E. Bock (advisor) Committee Member
  • streptococcus agalactiae
  • skizzle
  • fibrinolysis
  • plasminogen
Date of Defense 2010-08-12
Availability unrestricted
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.
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