Autotransporters: protein contortionists whose carboxyl termini translocate their own amino-terminal domains

Abstract

As originally described in a series of elegant experiments by Thomas Meyer and colleagues[ 1 Halter R. Pohlner J. Meyer T. EMBO J. 1984; 3: 1595-1601 PubMed Google Scholar ], the autotransporter, immunoglobulin A (IgA) protease, in Neisseria gonorrhoeae seemed like a quirky, one-off system for the secretion of an amino-terminal domain (passenger) through its own carboxy-terminal (transporter) inserted in the outer membrane of Gram-negative bacteria. In their excellent review, Henderson et al.[ 2 Henderson I.R. Navarro-Garcia F. Nataro J.P. Trends Microbiol. 1998; 6: 370-378 Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar ]have detailed the burgeoning field of these so-called type IV secretion systems[ 3 Genin S. Boucher C.A. Mol. Gen. Genet. 1994; 243: 112-118 Crossref PubMed Scopus (149) Google Scholar , 4 Pimenta, A. et al. (1997) in Unusual Routes for Protein Secretion (Kuchler, K., Holland, I.B. and Rubartelli, A., eds), pp. 1–48, R.G. Landes Google Scholar ], but have raised many more questions than anyone can yet answer about the precise mechanism involved. In particular, what remains completely unclear is how the hydrophilic passenger is targeted to and then translocated through the presumed β-barrel monomeric pore, which is formed by the carboxy-terminal of the autotransporter. Coincidentally, recent studies by Alan Finkelstein's group[ 5 Jakes K.S. et al. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 4321-4326 Crossref PubMed Scopus (33) Google Scholar ]with colicin Ia have come up with the equally surprising finding that even highly charged peptides can be translocated across lipid bilayers by the simplest of translocators—two downstream transmembrane domains—although this mechanism is also a complete mystery. Henderson et al.[ 2 Henderson I.R. Navarro-Garcia F. Nataro J.P. Trends Microbiol. 1998; 6: 370-378 Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar ]hint that the amino-terminal passenger of the autotransporter can be unfolded during transport. This requires verification, as it leads to two important questions: how is the unfolded state maintained and how does the transported domain then refold correctly and efficiently in the hostile external environment?