Molecular Biology and Evolution 19:718-727 (2002)
© 2002 Society for Molecular Biology and Evolution
Functional Diversification During Evolution of the Murine 
1-Proteinase Inhibitor Family: Role of the Hypervariable Reactive Center Loop
*Department of Biological Sciences, University of South Carolina;
Department of Cell and Molecular Biology, Roswell Park Cancer Institute
1-Proteinase inhibitor (1-PI) is a member of the serpin superfamily of serine proteinase inhibitors that are involved in the regulation of a number of proteolytic processes. 1-PI, like most serpins, functions by covalent binding to, and inhibition of, target proteinases. The interaction between 1-PI and its target is directed by the so-called reactive center loop (RCL), an 
20 residue domain that extends out from the body of the 1-PI polypeptide and determines the inhibitor's specificity. Mice express at least seven closely related 1-PI isoforms, encoded by a family of genes clustered at the Spi1 locus on chromosome 12. The amino acid sequence of the RCL region is hypervariable among 1-PIs, a phenomenon that has been attributed to high rates of evolution driven by positive Darwinian selection. This suggests that the various isoforms are functionally diverse. To test this notion, we have compared the proteinase specificities of individual 1-PIs from each of the two mouse species. As predicted from the positive Darwinian selection hypothesis, the various 1-PIs differ in their ability to form covalent complexes with serine proteinases, such as elastase, trypsin, chymotrypsin, and cathepsin G. In addition, they differ in their binding ability to proteinases in crude snake venoms. Importantly, the RCL region of the 1-PI polypeptide is the primary determinant of isoform-specific differences in proteinase recognition, indicating that hypervariability within this region drives the functional diversification of 1-PIs during evolution. The possible physiological benefits of 1-PI diversity are discussed.
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