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J. Biol. Chem., Vol. 263, Issue 32, 16626-16630, Nov, 1988
M Bruch, V Weiss and J Engel
Intact and proteolytically modified human serpins, alpha 1-proteinase
inhibitor, antithrombin III, alpha 1-antichymotrypsin, and C1 inhibitor,
were compared by circular dichroism, fluorescence spectroscopy, and
resistance against unfolding by guanidine HCl. The modified proteins were
prepared from the intact and active inhibitors by selective proteolytic
cleavage in their reactive site loops and tested for complete loss of
activity. Significant differences in the spectral properties between intact
and modified inhibitors indicate that a major conformational rearrangement
is triggered by the cleavage. This leads to a large increase in
conformational stability as demonstrated by large shifts of the transition
profiles recorded as a function of guanidine HCl concentration at 20
degrees C by circular dichroism at 220 nm. Intact inhibitors were unfolded
in two steps of about equal size centered at 0.8-1.7 and 2.5-3.5 M
concentrations of the denaturant, respectively. Under identical conditions
modified inhibitors are completely stable, and their denaturation occurs
only well above 4 M guanidine HCl in one or two steep transition steps.
From the similarity of the spectral changes and shifts in transition
profiles for all four serpins studied it is concluded that the
conformational changes and stabilization triggered by the modification hit
is an important common mechanistic feature of this class of inhibitors.
This is supported by the observation that ovalbumin, which is homologous
with the serpins but apparently lacks inhibitory activity, exhibits neither
spectral changes nor a significant change in stability upon proteolytic
modification.
Plasma serine proteinase inhibitors (serpins) exhibit major conformational changes and a large increase in conformational stability upon cleavage at their reactive sites
Department of Biophysical Chemistry, University of Basel, Switzerland.
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