Journal of Molecular Biology
Volume 293, Issue 3, 29 October 1999, Pages 449-455
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Communication
A 2.6 å structure of a serpin polymer and implications for conformational disease1

https://doi.org/10.1006/jmbi.1999.3184Get rights and content

Abstract

The function of the serpins as proteinase inhibitors depends on their ability to insert the cleaved reactive centre loop as the fourth strand in the main A β-sheet of the molecule upon proteolytic attack at the reactive centre, P1-P1′. This mechanism is vulnerable to mutations which result in inappropriate intra- or intermolecular loop insertion in the absence of cleavage. Intermolecular loop insertion is known as serpin polymerisation and results in a variety of diseases, most notably liver cirrhosis resulting from mutations of the prototypical serpin α1-antitrypsin. We present here the 2.6 Å structure of a polymer of α1-antitrypsin cleaved six residues N-terminal to the reactive centre, P7-P6 (Phe352-Leu353). After self insertion of P14 to P7, intermolecular linkage is affected by insertion of the P6-P3 residues of one molecule into the partially occupied β-sheet A of another. This results in an infinite, linear polymer which propagates in the crystal along a 2-fold screw axis. These findings provide a framework for understanding the uncleaved α1-antitrypsin polymer and fibrillar and amyloid deposition of proteins seen in other conformational diseases, with the ordered array of polymers in the crystal resulting from slow accretion of the cleaved serpin over the period of a year.

Section snippets

Protein data bank number

Coordinates have been deposited in the Protein Data Bank (accession number 18mb).

Acknowledgements

We thank Charles T. Esmon for providing the inactive thrombin. This work was supported by the Wellcome Trust (R.W.C., 039046; R.J.R. 050211) and by the NIH (J.A.H. HL09927). N.S.P. is supported by Wellcome Trust and NSERC studentships.

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