Journal
FASEB JOURNAL
Volume 34, Issue 1, Pages 619-630Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201901490RR
Keywords
fibrinolysis; plasmin; periodontitis; serpin; Tannerella forsythia
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Funding
- National Science Center (Krakow, Poland) [UMO-2015/17/B/NZ1/00666, UMO-2016/21/B/NZ1/00292]
- NIH/NIDCR [R21DE026280]
- Ministry of Science and Higher Education [1306/MOB/IV/2015/0]
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Tannerella forsythia is a periodontopathogen that expresses miropin, a protease inhibitor in the serpin superfamily. In this study, we show that miropin is also a specific and efficient inhibitor of plasmin; thus, it represents the first proteinaceous plasmin inhibitor of prokaryotic origin described to date. Miropin inhibits plasmin through the formation of a stable covalent complex triggered by cleavage of the Lys(368)-Thr(369) (P2-P1) reactive site bond with a stoichiometry of inhibition of 3.8 and an association rate constant (k(ass)) of 3.3 x 10(5) M(-1)s(-1). The inhibition of the fibrinolytic activity of plasmin was nearly as effective as that exerted by alpha(2)-antiplasmin. Miropin also acted in vivo by reducing blood loss in a mice tail bleeding assay. Importantly, intact T. forsythia cells or outer membrane vesicles, both of which carry surface-associated miropin, strongly inhibited plasmin. In intact bacterial cells, the antiplasmin activity of miropin protects envelope proteins from plasmin-mediated degradation. In summary, in the environment of periodontal pockets, which are bathed in gingival crevicular fluid consisting of 70% of blood plasma, an abundance of T. forsythia in the bacterial biofilm can cause local inhibition of fibrinolysis, which could have possible deleterious effects on the tooth-supporting structures of the periodontium.
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