Necrotic Flies

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Science  21 Mar 2003:
Vol. 299, Issue 5614, pp. 1815
DOI: 10.1126/science.299.5614.1815b

Serpins, like antithrombin and antitrypsin, inhibit serine proteases, and when they are lacking or mutated contribute to a range of disorders including hepatitis, emphysema, and thrombosis. Serpins undergo a conformational change that allows interaction with target proteases, and mutations that affect this mechanism lead to the formation of inactive serpin polymers. Green et al. studied Drosophila strains with mutations in the necrotic (nec) gene, which encodes a serpin homologous to antitrypsin. Amino acid substitutions equivalent to those found in human pathological variants were observed, and overexpression of the nec mutants induced early mortality. Drosophila may thus provide a model system to test therapeutics for human disease.

In an independent study, Rapa et al. identified a human antithrombin variant associated with early-onset thrombosis. Although inactive, the mutant displayed higher affinity for heparin, which normally catalyzes the conformational change that activates antithrombin. Thus, the mutant could sequester heparin and block normal serpin activation. — LDC

Development130, 1573 (2003); J. Biol. Chem. 10.1074/jbc.M300062200 (2003).

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