The biostructural pathology of the serpins: critical function of sheet opening mechanism.

Abstract

The serpins illustrate the way in which the study of a protein family as a whole can clarify the functions of its individual members. Although the individual serpins have become remarkably diversified by evolution they all share a common structural pathology. We have previously shown how plotting of the dysfunctional natural mutations of the serpins on a template structure defines the domains controlling the mobility of the reactive centre loop of the molecule. Here we compare these natural mutations with reciprocal mutations in recombinants that restore the inhibitory stability of a labile member of the family, plasminogen activator inhibitor-1 (PAI-1). The combined results emphasise the critical part played by residues involved in the sliding movement that opens the A-sheet to allow reactive loop insertion. It is concluded that changes in these residues provide the prime explanation for the ready conversion of PAI-1 to the inactive latent state. The consistency of the overall results gives confidence in predicting the likely consequences of mutations in individual serpins. In particular the two common polymorphic mutations present in human angiotensinogen are likely to affect molecular stability and hence may be contributory factors to the observed association with vascular disease.