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Structure of the trypsin induced serpin-type proteinase inhibitor, miropin (V367K/K368A mutant).
Structural highlights
FunctionPublication Abstract from PubMedEnduring host-microbiome relationships are based on adaptive strategies within a particular ecological niche. Tannerella forsythia is a dysbiotic member of the human oral microbiome that inhabits periodontal pockets and contributes to chronic periodontitis. To counteract endopeptidases from the host or microbial competitors, T. forsythia possesses a serpin-type proteinase inhibitor called miropin. While serpins from animals, plants, and viruses have been widely studied, those from prokaryotes have received only limited attention. Here we show that miropin uses the serpin-type suicidal mechanism. We found that similarly to a snap trap, the protein transits from a metastable native form to a relaxed triggered or induced form after cleavage of a reactive-site target bond in an exposed reactive-center loop. The prey peptidase becomes covalently attached to the inhibitor, is dragged 75A apart, and is irreversibly inhibited. This coincides with a large conformational rearrangement of miropin, which inserts the segment upstream of the cleavage site as an extra beta-strand in a central beta-sheet. Standard serpins possess a single target bond and inhibit selected endopeptidases of particular specificity and class. In contrast, miropin uniquely blocked many serine and cysteine endopeptidases of disparate architecture and substrate specificity owing to several potential target bonds within the reactive-center loop and to plasticity in accommodating extra beta-strands of variable length. Phylogenetic studies revealed a patchy distribution of bacterial serpins, incompatible with a vertical descent model. This finding suggests that miropin was acquired from the host through horizontal gene transfer, perhaps facilitated by T. forsythia's long and intimate association with the human gingiva. A structure-derived snap-trap mechanism of a multispecific serpin from the dysbiotic human oral microbiome.,Goulas T, Ksiazek M, Garcia-Ferrer I, Sochaj-Gregorczyk AM, Waligorska I, Wasylewski M, Potempa J, Gomis-Ruth FX J Biol Chem. 2017 May 16. pii: jbc.M117.786533. doi: 10.1074/jbc.M117.786533. PMID:28512127[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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