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    Fluorescence Correlation Spectroscopic Study of Serpin Depolymerization by Computationally Designed Peptides

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    Date
    2007
    Author
    Chowdhury, Pramit
    Wang, Wei
    Lavender, Stacey
    Bunagan, Michelle R.
    Klemke, Jason W.
    Tang, Jia
    Saven, Jeffrey G.
    Cooperman, Barry S.
    Gai, Feng
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    Abstract
    Abstract
    Members of the serine proteinase inhibitor (serpin) family play important roles in the inflammatory and coagulation cascades. Interaction of a serpin with its target proteinase induces a large conformational change, resulting in insertion of its reactive center loop (RCL) into the main body of the protein as a new strand within β-sheet A. Intermolecular insertion of the RCL of one serpin molecule into the β-sheet A of another leads to polymerization, a widespread phenomenon associated with a general class of diseases known as serpinopathies. Small peptides are known to modulate the polymerization process by binding within β-sheet A. Here, we use fluorescence correlation spectroscopy (FCS) to probe the mechanism of peptide modulation of α1-antitrypsin (α1-AT) polymerization and depolymerization, and employ a statistical computationally-assisted design strategy (SCADS) to identify new tetrapeptides that modulate polymerization. Our results demonstrate that peptide-induced depolymerization takes place via a heterogeneous, multi-step process that begins with internal fragmentation of the polymer chain. One of the designed tetrapeptides is the most potent antitrypsin depolymerizer yet found.
    Citation:
    Chowdhury, P.; Wang, W.; Lavender, S.; Bunagan, M.R.; Klemke, J.W.; Tang, J.; Saven, J.G.; Cooperman, B.S.; Gai, F. "Fluorescence Correlation Spectroscopic Study of Serpin Depolymerization by Computationally Designed Peptides," Journal of Molecular Biology, 2007, 369, 462-473.
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    URI
    http://dx.doi.org/10.1016/j.jmb.2007.03.042
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