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Biochem. Soc. Symp. (2003) 70, (163–178) (Printed in Great Britain)
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Chapter 14
How serpins change their fold for better and for worse |
| Robin W.Carrell1 and James A. Huntington |
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| University of Cambridge, Department of Haematology, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, U.K.
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1To whom correspondence should be addressed (e-mail rwc1000@cam.ac.uk).
Abstract:
The serpins differ from the many other families of serine protease
inhibitors in that they undergo a profound change in topology in order to
entrap their target protease in an irreversible complex. The solving of the structure
of this complex has now provided a video depiction of the changes
involved. Cleavage of the exposed reactive centre of the serpin triggers an
opening of the five-stranded A-sheet of the molecule, with insertion of the
cleaved reactive loop as an additional strand in the centre of the sheet. The drastic
displacement of the acyl-linked protease grossly disrupts its active site and
gives an overall loss of 40% of ordered structure. This ability to provide effectively
irreversible inhibition explains the selection of the serpins to control the
proteolytic cascades of higher organisms. The conformational mechanism provides
another advantage in its potential to modulate activity. Sequential
crystallographic structures now provide clear depictions of the way antithrombin
is activated on binding to the heparans of the microcirculation, and how
evolution has utilized this mobile mechanism for subtle variations in activity.
The complexity of these modulatory mechanisms is exemplified by heparin
cofactor II, where the change in fold is seen to trigger multiple allosteric effects.
The downside of the mobile mechanism of the serpins is their vulnerability to
aberrant intermolecular b-linkages, resulting in various disorders from cirrhosis
to thrombosis. These provide a well defined structural prototype for the
new entity of the conformational diseases, including the common dementias, as
confirmed by the recent identification of the familial neuroserpin dementias.
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