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Edited by Robert Huber, Max Planck Institute for Biochemistry, Planegg-Martinsried, Germany, and approved August 6, 2010 (received for review April 8, 2010)
↵1U.I.E., J.F., and E.M. contributed equally to this work.
Abstract
The serpinopathies result from the ordered polymerization of mutants of members of the serine proteinase inhibitor (serpin) superfamily. These polymers are retained within the cell of synthesis where they cause a toxic gain of function. The serpinopathies are exemplified by inclusions that form with the common severe Z mutant of α1-antitrypsin that are associated with liver cirrhosis. There is considerable controversy as to the pathway of serpin polymerization and the structure of pathogenic polymers that cause disease. We have used synthetic peptides, limited proteolysis, monoclonal antibodies, and ion mobility-mass spectrometry to characterize the polymerogenic intermediate and pathological polymers formed by Z α1-antitrypsin. Our data are best explained by a model in which polymers form through a single intermediate and with a reactive center loop-β-sheet A linkage. Our data are not compatible with the recent model in which polymers are linked by a β-hairpin of the reactive center loop and strand 5A. Understanding the structure of the serpin polymer is essential for rational drug design strategies that aim to block polymerization and so treat α1-antitrypsin deficiency and the serpinopathies.
Footnotes
- 2To whom correspondence should be addressed. E-mail: dal16{at}cam.ac.uk.
Author contributions: U.I.E., J.F., E.M., and D.A.L. designed research; U.I.E., J.F., E.M., and J.P. performed research; U.I.E., J.F., E.M., J.T., and C.V.R. contributed new reagents/analytic tools; U.I.E., J.F., E.M., B.G., M.F.B., and D.A.L. analyzed data; and U.I.E. and D.A.L. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Defining the mechanism of polymerization in the serpinopathies
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