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Mol Cell. 2016 Apr 7;62(1):47-62. doi: 10.1016/j.molcel.2016.03.018.

Calcium-Driven Folding of RTX Domain β-Rolls Ratchets Translocation of RTX Proteins through Type I Secretion Ducts.

Author information

1
Institute of Microbiology, ASCR, v.v.i., Videnska 1083, 14220 Prague, Czech Republic.
2
Institute of Microbiology, ASCR, v.v.i., Videnska 1083, 14220 Prague, Czech Republic; Faculty of Science, Charles University in Prague, Vinicna 5, 128 44 Prague, Czech Republic.
3
Institute of Organic Chemistry and Biochemistry, ASCR, v.v.i., Flemingovo nam. 2, 16610 Prague, Czech Republic.
4
Hamburg Outstation, European Molecular Biology Laboratory, c/o DESY, Notkestrasse 85, D-22607 Hamburg, Germany.
5
Institute of Biotechnology, ASCR, v.v.i., Videnska 1083, 14220 Prague, Czech Republic.
6
Institute of Microbiology, ASCR, v.v.i., Videnska 1083, 14220 Prague, Czech Republic. Electronic address: sebo@biomed.cas.cz.

Abstract

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.

PMID:
27058787
DOI:
10.1016/j.molcel.2016.03.018
[Indexed for MEDLINE]
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