Abstract
Enduring 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. Although 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, similar 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 75 Å 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 β-strand in a central β-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 β-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 the long and intimate association of T. forsythia with the human gingiva.
Highlights
Enduring host-microbiome relationships are based on adaptive strategies within a particular ecological niche
We know remarkably little about their diversity, variation, and evolution, so unveiling the molecular mechanisms they have derived to adapt to us and to microbial competitors is key to our understanding of both healthy symbiosis and pathogenic dysbiosis
We here describe for the first time the mechanism of action of the bacterial serpin that enables T. forsythia to better thrive in the harsh and crowded human oral cavity
Summary
Enduring host-microbiome relationships are based on adaptive strategies within a particular ecological niche. PD is a chronic inflammatory disease driven by bacteria in the subgingival dental plaque, which occurs in 5–20% of the adult population worldwide [6] It is mainly caused by the “red complex” [7], a bacterial consortium including Tannerella forsythia, Porphyromonas gingivalis, and Treponema denticola, which exclusively reside in periodontal pockets [8]. The three red-complex members were recently identified in ϳ49,000-year-old dental calculus samples from Homo neanderthaliensis [12], which suffered from dental caries and PD like modern humans [13] and likely interbred with them across Eurasia [14] The persistence of these bacterial species within the human oral microbiome can only be explained by the development of adaptive mechanisms to thrive in a harsh environment, which is characterized by competing microorganisms and host defenses
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