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    • Graduate School - MU Theses and Dissertations (MU)
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    • 2008 Dissertations (MU)
    • 2008 MU dissertations - Access restricted to UM
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    Discovery of epitopes governing MMP-12 specificity for fibrillar substrates : BINDSIght, a method for determining specific sites of substrate surface interactions

    Palmier, Mark O., 1951-
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    [PDF] research.pdf (10.52Mb)
    Date
    2008
    Format
    Thesis
    Metadata
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    Abstract
    [ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] What determines MMP-12 elastase activity? We have found that the fibrillar substrate specificity of MMP-12 involves surfaces ranging beyond the intensively studied active site cleft and S1' pocket. This was achieved by discovery of a novel global analysis method. The BINDSIght method of discovering sites governing specificity uses a combination of bioinformatic and NMR detected assays. Using this new technology to guide a mutagenesis study, new light has been shed on the substrate specificity of MMP-12 toward elastin and collagen (V). Using a novel kinetic methodology I developed for analyzing time domain progress curves, the mutational lesions were compared to wild type MMP-12 by activity assays. Residues F202, T205 and H206 in the strand V to helix B loop appear to be significant factors in the binding and catalytic rate of fluorescent mimics of collagen V and elastin. Surprisingly, the unprimed site residues F185 and G227 show up as important keys in modifying activity on these fibrillar substrates. In the primed site region we show that T239 and K241 also directly contribute to MMP-12 elastin and collagen V activity. Mutating these residues significantly impairs activity upon elastin and collagen V substrate mimics without compromising activity upon a small broad range MMP substrate. Since the entire family of MMPs differ very little in sequence of the active site, it makes sense that exosites contribute to MMP-12 activity.
    URI
    https://hdl.handle.net/10355/9192
    https://doi.org/10.32469/10355/9192
    Degree
    Ph. D.
    Thesis Department
    Biochemistry (MU)
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    Access is limited to the campuses of the University of Missouri.
    Collections
    • 2008 MU dissertations - Access restricted to UM
    • Biochemistry electronic theses and dissertations (MU)
    • Biochemistry electronic theses and dissertations (MU)

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