The Spn4 gene from Drosophila melanogaster is a multipurpose defence tool directed against proteases from three different peptidase families
Résumé
By alternative use of four reactive site loop coding exon cassettes, the serpin gene Spn4 from Drosophila melanogaster was proposed to enable the synthesis of multiple protease inhibitor isoforms, one of which has been shown to be a potent inhibitor of human furin. Here, we have investigated the inhibitory spectrum of all Spn4 reactive site loop variants. The analyses indicate that the Spn4 gene encodes inhibitors that may inhibit serine proteases of the subtilase family (S8), the chymotrypsin family (S1), and the papain-like cysteine protease family (C1), most of them at high rates. Thus, a cohort of different protease inhibitors is generated simply by grafting enzyme-adapted reactive site loop sequences onto a single serpin scaffold, even though the target proteases contain different types and/or a varying order of catalytic residues and are descendents of different phylogenetic lineages. Since all of the Spn4 reactive site loop isoforms are produced as intracellular residents and additionally as variants destined for export or associated with the secretory pathway, the Spn4 gene represents a versatile defense tool kit that may provide multiple antiproteolytic functions.
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