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Elucidating the Ferritin-High Molecular Weight Kininogen Domain 5 Interaction

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Angiogenesis, the formation of new vessels from existing blood vessels, is essential for such physiological processes as wound healing and tumor growth. It is a highly regulated process, as numerous endogenous angiogenic modulators exist that both positively and negatively control vascularization. When the balance of modulators is altered, pathologic angiogenesis can occur. One such modulator is derived from high molecular weight kininogen, or HK, a plasma protein involved in the intrinsic blood coagulation pathway. Once HK is cleaved by kallikrein or another protease, HKa is produced, which is capable of reversibly binding to endothelial cells in the presence of Zn2+ and inhibiting angiogenesis. This action has been narrowed to the 109–amino acid domain 5 (HK5), a functional domain that binds to numerous endothelial cell surface receptors. By binding to domains 2 and 3 of the urokinase–type plasminogen activator receptor (uPAR), HK5 disrupts the interaction between uPAR and vitronectin, which activates the uPAR signaling pathway. Inhibiting the vitronectin–uPAR interaction causes an inhibition of endothelial cell adhesion, migration, tube formation and proliferation as well as inducing apoptosis. The minimum region of HK5 needed to induce antiangiogenic effects is a 29 residue stretch at the C–terminal end that has similar effects to HK5. The HK5 domain also binds to ferritin, an iron storage protein, which can inhibit the antiangiogenic effects of HK5. How ferritin inhibits the antiangiogenic effects of HK5 remains an important question.
high molecular weight kininogen
protein-protein interactions
structural biology
Huhn, Annissa J. (author)
Hollis, Thomas (committee chair)
Torti, Suzy V (committee member)
Lowther, W. Todd (committee member)
Lyles, Douglas S (committee member)
Metheny-Barlow, Linda J (committee member)
2013-01-09T09:35:18Z (accessioned)
2013-07-09T08:30:10Z (available)
2012 (issued)
Biochemistry and Molecular Biology (discipline)
2013-07-09 (terms)
http://hdl.handle.net/10339/37668 (uri)
en (iso)
Wake Forest University
Elucidating the Ferritin-High Molecular Weight Kininogen Domain 5 Interaction

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