Date of this Version
Journal of Molecular Biology
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 beta-sheet A. Intermolecular insertion of the RCL of one serpin molecule into the beta-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 beta-sheet A. Here, we use fluorescence correlation spectroscopy (FCS) to probe the mechanism of peptide modulation of alpha(1)-antitrypsin (alpha(1)-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.
© 2007. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Amino Acid Sequence, Models, Molecular, Peptides, Protein Structure, Quaternary, Serpins, Spectrometry, Fluorescence, alpha 1-Antitrypsin
Chowdhury, P., Wang, W., Lavender, S., Bunagan, M., Klemke, J. W., Tang, J., Saven, J. G., Cooperman, B. S., & Gai, F. (2007). Fluorescence Correlation Spectroscopic Study of Serpin Depolymerization by Computationally Designed Peptides. Journal of Molecular Biology, 369 (2), 462-473. http://dx.doi.org/10.1016/j.jmb.2007.03.042
Date Posted: 07 December 2016
This document has been peer reviewed.