The effects of reactive centre loop length upon serpin polymerisation

The clinical effects of serpin polymerisation include thromboembolism, emphysema, and liver disease. A thorough understanding of serpin polymerisation mechanisms and the structures involved will permit the rational design of therapeutic polymerisation inhibitors. Here we show that serpin polymerisation can be delayed by extending the length of the serpin reactive centre loop. The heat stability of three chimeric serpins was examined. One of them, an active alpha(1)-antitrypsin variant with a reactive centre loop C-terminal extension of four amino acid residues, was shown to have increased resistance to inactivation by polymerisation. This variant could also form serpin/peptide binary complexes with a reactive centre loop peptide, which indicates that the increase in thermostability was not due to the A-beta-sheet being unable to accept reactive centre loop residues, an essential requirement for polymerisation. Rather we conclude that the additional residues within the reactive centre loop delay the release of strand 1C from the C-sheet, a process essential for polymer formation. (C) 1997 Academic Press.