Calcium-binding RTX proteins are equipped with C-terminal secretion signals and translocate from the Ca(2+)-depleted cytosol of Gram-negative bacteria directly into the Ca(2+)-rich external milieu, passing through the "channel-tunnel" ducts of type I secretion systems (T1SSs). Using Bordetella pertussis adenylate cyclase toxin, we solved the structure of an essential C-terminal assembly that caps the RTX domains of RTX family leukotoxins. This is shown to scaffold directional Ca(2+)-dependent folding of the carboxy-proximal RTX repeat blocks into β-rolls. The resulting intramolecular Brownian ratchets then prevent backsliding of translocating RTX proteins in the T1SS conduits and thereby accelerate excretion of very large RTX leukotoxins from bacterial cells by a vectorial "push-ratchet" mechanism. Successive Ca(2+)-dependent and cosecretional acquisition of a functional RTX toxin structure in the course of T1SS-mediated translocation, through RTX domain folding from the C-terminal cap toward the N terminus, sets a paradigm that opens for design of virulence inhibitors of major pathogens.

Hamburg Outstation European Molecular Biology Laboratory c o DESY Notkestrasse 85 D 22607 Hamburg Germany

Institute of Biotechnology ASCR v v i Videnska 1083 14220 Prague Czech Republic

Institute of Microbiology ASCR v v i Videnska 1083 14220 Prague Czech Republic

Institute of Microbiology ASCR v v i Videnska 1083 14220 Prague Czech Republic; Faculty of Science Charles University Prague Vinicna 5 128 44 Prague Czech Republic

Institute of Organic Chemistry and Biochemistry ASCR v v i Flemingovo nam 2 16610 Prague Czech Republic

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