The symptoms of many bacterial diseases are due largely to the actions of toxic proteins released by the bacteria (diphtheria, anthrax, cholera, and tetanus toxins are well known examples). We study these toxins with the goals of understanding the biochemical basis of bacterial disease; gaining insight into how proteins cross membranes; and developing new pharmaceuticals. The most potent toxins act by penetrating into mammalian cells and modifying target substrates within the cytosol. Their actions generally involve four steps: (i) binding to receptors; (ii) endocytosis of the toxin-receptor complex; (iii) translocation of the enzymic part across a membrane, into the cytosol; and (iv) enzymic methods to generate detailed models of each step in toxin action. How these structurally unrelated toxins insert into membranes under the influence of the low pH of the endosomal compartment, and translocate their enzymic moieties across the endosomal membrane represents a problem of broad interest. Crystallographic structures of the native proteins provide a framework for our studies. Genetically modified, nontoxic forms of these toxins may be used as transporters for heterologous proteins and peptides into cells. We are using anthrax toxin to engineer a new type of vaccines that stimulates the formation of cytotoxic T lymphocytic (CTL) responses, as opposed to antibody formation. CTL-based vaccines may be useful against a variety of diseases which have heretofore been thought to be beyond the realm of vaccination.
Publications
Lacy DB, Lin HC, Melnyk RA, Schueler-Furman O, Reither L, Cunningham K, Baker D, Collier RJ.A model of anthrax toxin lethal factor bound to protective antigen.Proc Natl Acad Sci U S A 2005 Nov 8;102(45):16409-14. 16251269
Wolfe JT, Krantz BA, Rainey GJ, Young JA, Collier RJ.Whole-cell voltage clamp measurements of anthrax toxin pore current.J Biol Chem 2005 Sep 23. 16183642
Krantz BA, Melnyk RA, Zhang S, Juris SJ, Lacy DB, Wu Z, Finkelstein A, Collier RJ.A phenylalanine clamp catalyzes protein translocation through the anthrax toxin pore.Science 2005 Jul 29;309(5735):777-81. 16051798
Zhang S, Finkelstein A, Collier RJ.Evidence that translocation of anthrax toxin's lethal factor is initiated by entry of its N terminus into the protective antigen channel.Proc Natl Acad Sci U S A 2004 Nov 30;101(48):16756-61. 15548616
